Final Weeks to Register! Record Attendance this Year Drug Discovery Chemistry TENTH ANNUAL APRIL 21 - 23, 2015 HILTON SAN DIEGO RESORT & SPA | SAN DIEGO, CA PLENARY KEYNOTES Chemotype Coverage in Fragment, Phenotypic, and Deorphanization Screens Brian K. Shoichet, Ph.D., University of California, San Francisco Fragment-Based Drug Discovery: A Fifteen Year (Re-)Evolution Harren Jhoti, Ph.D., Astex Pharmaceuticals EVENT FEATURES • More than 100 presentations • 500+ high-level participants • 70+ posters • Interactive roundtable, breakout & panel discussions • “Track-hop” between concurrent meetings • Exclusive exhibit & poster viewing hours • Dedicated networking opportunities • 8 interactive short courses APRIL 21 - 22 SIXTH ANNUAL Kinase Inhibitor Chemistry TENTH ANNUAL Fragment-Based Drug Discovery THIRD ANNUAL Macrocyclics and Constrained Peptides SECOND ANNUAL Epigenetic Inhibitor Discovery EIGHTH ANNUAL Protein-Protein Interactions SIXTH ANNUAL Inflammation Inhibitors APRIL 22 - 23 TOMORROW’S SMALL MOLECULES FOR OPTIMIZING THERAPEUTICS 10 th Annual 2006-2015 A Decade of Discovery PREMIER SPONSOR DrugDiscoveryChemistry.com Cover Short Courses Sponsor & Exhibit Opportunities Fragment-Based Drug Discovery Macrocylics and Constrained Peptides Kinase Inhibitor Chemistry Conference-at-a-Glance Plenary Keynotes Distinguished Faculty Hotel & Travel Information Epigenetic Inhibitor Discovery Welcome Inflammation Inhibitors Protein-Protein Interactions Registration Information Click Here to Register Online! DrugDiscoveryChemistry.com Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA 02494 www.healthtech.com Final Weeks to Register! Record Attendance this Year
Transcript
Final Weeks to Register!
Record Attendance this Year
Drug Discovery Chemistry
TENTH ANNUAL
APRIL 21 - 23, 2015 HILTON SAN DIEGO RESORT & SPA | SAN DIEGO, CA
PLENARY KEYNOTES Chemotype Coverage in Fragment, Phenotypic, and Deorphanization ScreensBrian K. Shoichet, Ph.D., University of California, San Francisco
Fragment-Based Drug Discovery: A Fifteen Year (Re-)EvolutionHarren Jhoti, Ph.D., Astex Pharmaceuticals
KINASE INHIBITOR CHEMISTRY MACROCYCLICS AND CONSTRAINED PEPTIDES
FRAGMENT-BASED DRUG DISCOVERY
THURSDAY, APRIL 23
KINASE INHIBITOR CHEMISTRY MACROCYCLICS AND CONSTRAINED PEPTIDES
FRAGMENT-BASED DRUG DISCOVERY
COMBINED PLENARY SESSION
COMBINED PLENARY SESSION
WELCOME RECEPTION IN THE EXHIBIT HALL WITH POSTER VIEWING
CONTINENTAL BREAKFAST & BREAKOUT DISCUSSIONS
DINNER SHORT COURSES*
BREAKOUT DISCUSSIONS
CELEBRATORY 10TH ANNUAL REFRESHMENT BREAK IN EXHIBIT HALL WITH POSTER VIEWING
WALK AND TALK LUNCHEON IN THE EXHIBIT HALL WITH POSTER VIEWING
CONFERENCE-AT-A-GLANCE
*Separate registration is required
Cover
Short Courses
Sponsor & Exhibit Opportunities
Fragment-Based Drug Discovery
Macrocylics and Constrained Peptides
Kinase Inhibitor Chemistry
Conference-at-a-Glance
Plenary Keynotes
Distinguished Faculty
Hotel & Travel Information
Epigenetic Inhibitor Discovery
Welcome
Inflammation Inhibitors
Protein-Protein Interactions
Registration Information
Click Here to Register Online!
DrugDiscoveryChemistry.com
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PLENARY KEYNOTES
Tuesday, April 21 – 4:30pmChemotype Coverage in Fragment, Phenotypic, & Deorphanization ScreensBrian K. Shoichet, Ph.D., Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco
The numbing size of chemical space shouldn’t prevent us from asking what screening libraries are missing relative to what we know to be biologically relevant. I explore the impact of chemotype representation on inhibitor discovery, fragment-based screens, whole organism phenotypic screens, and screens to deorphanize enzymes and GPCRs. Each case is framed by rough calculation and illustrated by specific experimental results. The libraries that result differ as much as the goals of the screen, but specific limits and optimization strategies emerge.
Thursday, April 23 – 8:30amFragment-Based Drug Discovery: A Fifteen Year (Re-)Evolution Harren Jhoti, Ph.D., President & CEO, Astex Pharmaceuticals
Fragment-based discovery has now been successfully established as an alternative approach to HTS and has produced multiple
drug candidates that are in clinical trials. Some of the appealing features of the approach include the ability to efficiently sample chemical space and to produce drug candidates that have superior physicochemical properties. In this talk I will provide a perspective on how Fragment-Based drug discovery evolved over the last 15 years and challenged conventional thinking in Drug Discovery.
TRACK-HOPPINGAttendees at Drug Discovery Chemistry are encouraged to “track-hop” between concurrent conference tracks. Register for one conference and gain access to three concurrent conference tracks, or for the best value, register for two conferences and gain access to all six conference tracks.
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PREMIER SPONSOR
For sponsorship and exhibit information, please contact: Carolyn Benton, Business Development ManagerPhone: (+1) [email protected]
CORPORATE SPONSORS
CORPORATE SUPPORT SPONSOR
WELCOME TO DRUG DISCOVERY CHEMISTRYCambridge Healthtech Institute’s Drug Discovery Chemistry, now in its 10th year, has established itself as a leading conference for medicinal chemists working in pharma and biotech. This three day event focuses on discovery and optimization challenges of small molecule drug candidates, and offers many exciting opportunities for scientists to move between concurrent conference tracks to create a unique program according to personal interests.
New this year are two Plenary Keynote sessions where all participants come together to hear a well-established scientist discuss pioneering work of interest to all discovery chemists and biologists. More information on our Plenary Keynotes can be found on page 2.
Based on last year’s record attendance and overwhelming positive delegate feedback, we are pleased to announce the topics for the 2015 conference tracks. Inflammation Inhibitors, Protein-Protein Interactions, and Epigenetic Inhibitor Discovery will take place in the first half of the event while the second half will feature Kinase Inhibitor Chemistry, Macrocyclics and Constrained Peptides, and Fragment-Based Drug Discovery.
We also offer ten pre-conference and dinner short courses. New this year is a course on Bromodomains and another on the Ubiquitin Proteasome System. Designed to be instructional and interactive, short courses are a great introduction for those new to a particular discipline or as a refresher for those who want to brush up on their knowledge.
Learning opportunities are not limited to podium presentations as delegates participate in informal roundtable breakout sessions and expert panel discussions. In addition, we have dedicated and robust poster sessions in the exhibit hall, featuring cutting-edge chemistry, technologies, and services.
We invite you to review this brochure to see how this great lineup of speakers and synergistic topics come together to create the leading event in drug discovery chemistry where scientists from all levels and settings can enjoy networking and spontaneous face-to-face interactions with one another.
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Short Courses* *Separate registration is required
MONDAY, APRIL 20
MORNING COURSE | 10:00 AM – 1:00 PM
SC1: Trends in Physical Properties of DrugsInstructor: Terry Stouch, Ph.D., President, R&D, Science for Solutions, LLC• Properties important for enhanced efficacy, delivery, and formulation• pKa, tautomerism, crystallization, others• Computational prediction: What works - what doesn’t• Experimental best practices
AFTERNOON COURSES | 2:30 – 5:30 PM
SC2: GPCR Structure-Based Drug DiscoveryInstructor: Aaron Thompson, Ph.D., Scientist II, Department of Structural Biology, Dart Neuroscience; former Postdoctoral Fellow, Ray Stevens’ Laboratory, The Scripps Research InstituteMatthew Eddy, Ph.D., Post-doctoral Fellow, Ray Stevens Laboratory, University of Southern California• Review of recent structures and their lessons• Dealing with conformational states• Antibodies as probes for structure
SC3: Molecular Interactions and Drug DesignInstructor: Maricel Torrent, Ph.D., Senior Scientist, AbbVie• Drug design principles generally applicable to all medicinal
chemistry programs• Interpretation of atomic-level protein X-ray and modeled structures of
binding modes• Understanding the relative amounts of potency gain from
different interactions• Case studies illustrate all of the design strategies
DINNER COURSES | 6:00 – 9:00 PM
SC5: Analyzing and Rationalizing Protein-Peptide Interactions for Designing Peptide and Peptidomimetic TherapeuticsInstructor: Rocky Goldsmith, Ph.D., Applications Scientist, Chemical Computing Group• Computer-aided methods using the MOE platform for protein-peptide
analysis, virtual peptide design and screening• Active site visualization, protein-peptide 3D contact analysis and 2D
interaction diagrams• Calculating molecular surfaces, electrostatic hot-spots and protein
properties to help guide peptide optimization• Modifying peptides in the active site• Applying ‘Residue Scan’ of non-natural amino acids for
peptidomimetic design
SC6: Immunology Basics for ChemistsInstructors: Seng-Lai “Thomas” Tan, Ph.D., Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc.Songqing Na, Ph.D., Senior Scientist, Biotechnology & Autoimmunity Res-AME, Eli Lilly and Company• Review of immune system’s cellular players• Review of inflammatory process• Autoimmune & inflammation-related diseases• Current treatment landscape and promising drug targets
“The Drug Discovery Chemistry conference offers a compact, dynamic event over three days that allows the scientific community an excellent opportunity
to stay aware of current trends.”Kenneth D., Director, FLAMMA
Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA 02494www.healthtech.com
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Short Courses* *Separate registration is required
WEDNESDAY, APRIL 22
DINNER COURSES | 6:30 – 9:00 PM
SC7: Macrocycles in Drug Discovery: Opportunities, Challenges and StrategiesInstructors: Mark L. Peterson, Ph.D., COO, Cyclenium Pharma, Inc.Eric Marsault, Ph.D., Professor, Pharmacology, University of Sherbrooke• Unique characteristics of macrocycles• Synthesizing and screening macrocyclic compound libraries• Pros and cons of each methodology• Drug discovery and development examples and challenges for
macrocyclic molecules
SC8: Advancing Tools and Technologies for Fragment-Based DesignInstructors: Daniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.Edward R. Zartler, Ph.D., President & CSO, Quantum Tessera Consulting• Why fragments – pros and cons• What makes a good fragment• What to do with a fragment – growing, linking, and more• Design of fragment libraries• Importance of using orthogonal/multiple screening method
SC9: Introduction to Targeted Covalent InhibitorsInstructors: Mark Schnute, Ph.D., Associate Research Fellow, Biotherapeutics Chemistry & Immunoscience Research, Pfizer Global R&DChristoph Zapf, Ph.D., Principal Scientist, Worldwide Medicinal Chemistry, Pfizer Research Labs• Overview of covalent drugs, irreversible and reversible inhibitors
including recent clinical examples• Biochemical analysis of covalent inhibitors• Design considerations for targeted covalent inhibitors• De-risking covalent inhibitors• Mechanism of drug resistance• Panel discussion/Q&A
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DISTINGUISHED FACULTY OF DRUG DISCOVERY CHEMISTRY 2015 Plenary KeynotesHarren Jhoti, Ph.D., Astex PharmaceuticalsBrian K. Shoichet, Ph.D., University of California, San FranciscoAlain Ajamian, Ph.D., Chemical Computing GroupMichelle Arkin, Ph.D., University of California, San Francisco Yuko Ariza, Ph.D., Ono Pharmaceutical Paramjit Arora, Ph.D., New York UniversityDavid Barda, Ph.D., Eli Lilly and CompanyDoug C. Beshore, Ph.D., Merck Research LaboratoriesPhillip Black, Ph.D., Senior Scientist, Discovery Services, Charles RiverJustin Bower, Ph.D., Beatson UniversityNunzio Bottini, M.D., Ph.D., La Jolla Institute for Allergy and Immunology Scott Breining, Ph.D., Asinex CorporationRogier C. Buijsman, Ph.D., Netherlands Translational Research Center B.V. (NTRC)Amedeo Caflisch, Ph.D., University of ZurichJianhua Chao, Ph.D., Biogen IdecAlessio Ciulli, Ph.D., University of DundeeSeth M. Cohen, Ph.D., University of California, San DiegoMary Ellen Digan, Ph.D., Novartis Institutes for BioMedical Research, Inc.Kenneth W. Duncan, Ph.D., EpizymeDonald Durden, M.D., Ph.D., UCSD School of Medicine and SignalRx PharmaceuticalsJörg Eder, Ph.D., Novartis Institutes for BioMedical ResearchDaniel A. Erlanson, Ph.D., Carmot Therapeutics, Inc.David P. Fairlie, Ph.D., University of QueenslandRudi Fasan, Ph.D., University of RochesterBenjamin Fauber, Ph.D., GenentechBarry Finzel, Ph.D., University of MinnesotaJiping Fu, Ph.D., NovartisAndrei Gartel, Ph.D, University of Illinois, Chicago Claire M. Gelfman, Ph.D., Ora, Inc.Rocky Goldsmith, Ph.D., Chemical Computing GroupMark Hixon, Ph.D., TakedaJan Hoflack, Ph.D., Oncodesign Biotechnology
Roderick E. Hubbard, Ph.D., Vernalis Research and University of YorkAndrew L. Hopkins, DPhil, University of DundeeHaitao (Mark) Ji, Ph.D., University of UtahTed W. Johnson, Ph.D., Pfizer OncologyRobert M. Jones, Ph.D., Arena PharmaceuticalsJan Kihlberg, Ph.D., Uppsala University, SwedenRoman Kombarov, Ph.D., Asinex CorporationAlexandr P. Kornev, Ph.D., University of California, San DiegoPeter Kutchukian, Ph.D., MerckRavi G. Kurumbail, Ph.D., PfizerTatiana Kutateladze, Ph.D., University of ColoradoDavid Langley, Ph.D., Bristol-Myers Squibb Co.Chenglong Li, Ph.D., The Ohio State University Comprehensive Cancer CenterSpiro Liras, Ph.D., PfizerBrian Lohse, Ph.D., University of CopenhagenKaren Maegley, Ph.D., Pfizer OncologySteven Magnuson, Ph.D., GenentechRoman Manetsch, Ph.D., Northeastern UniversityElizabeth Martinez, Ph.D., University of Texas Southwestern Medical CenterAndreas Marzinzik, Ph.D., Novartis Institutes for BioMedical ResearchEric Marsault, Ph.D., University of SherbrookeTill Maurer, Ph.D., Structural Biology, GenentechShelli McAlpine, Ph.D., University of New South Wales Chris McBride, TakedaJohn A. McCauley, Ph.D., MerckCampbell McInnes, Ph.D., University of South CarolinaMark McCoy, Ph.D., Merck Troy Messick, Wistar InstituteGerhard Mueller, Ph.D., MercaChem BVChudi Ndubaku, Ph.D., GenentechZaneta Nikolovska-Coleska, Ph.D., University of Michigan Medical SchoolJulen Oyarzabal, Ph.D., University of NavarraWylie Palmer, Ph.D., MD Anderson Cancer Center
Joe Patel, Ph.D., AstraZenecaSnahel Patel, Genentech, Inc.Zhonghua Pei, Ph.D., GenentechMark L. Peterson, Ph.D., Cyclenium Pharma, Inc.Andrew Petros, Ph.D., AbbVieOliver Plettenburg, Ph.D., Sanofi-AventisKamal Puri, Ph.D., Gilead Sciences, Inc.Nir Qvit, Ph.D., Stanford UniversityMark Sabat, Ph.D., Takeda Mark Schnute, Ph.D., Pfizer Global R&DMarkus Seeliger, Ph.D., Stony Brook UniversityMichael H. Serrano-Wu, Ph.D., Broad InstituteCynthia Shafer, Ph.D., Novartis Institutes for BioMedicalWoody Sherman, Ph.D., SchrödingerGregg Siegal, Ph.D., ZoBioDan Sindhikara, Senior Scientist, Structure-based ADME/Macrocycles, SchrödingerYongcheng Song, Ph.D., Baylor College of MedicineAlexander Statsyuk, Ph.D., Northwestern UniversityTerry Stouch, Ph.D., Science for Solutions, LLCRamzi Sweis, Ph.D., AbbVie, Inc.Seng-Lai “Thomas” Tan, Ph.D., EMD SeronoAlex Taylor, Ph.D., Senior Scientist, Medicinal Chemistry, Constellation PharmaceuticalsNicholas Terrett, Ph.D., EnsembleAaron Thompson, Ph.D., Dart NeuroscienceMaricel Torrent, Ph.D., AbbVieDouglas A. Treco, Ph.D., Ra Pharmaceuticals, Inc.Sandor Vajda, Ph.D., Boston UniversityHuanchen Wang, Ph.D., NIH Longcheng Wang, Ph.D., PharmacyclicsScot R. Weinberger, Molecular Sensing, Inc.Adrian Whitty, Ph.D., Boston UniversityAnthony William, Ph.D., A*STAR-ICESAlison Woolford, Ph.D., Astex PharmaceuticalsHang Hubert Yin, Ph.D., University of ColoradoChristoph Zapf, Ph.D., Pfizer Research LabsEdward R. Zartler, Ph.D., Quantum Tessera ConsultingZhihao Zhuang, Ph.D., University of Delaware
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Inflammation InhibitorsSmall Molecule and Macrocyclic Approaches
SIXTH ANNUAL APRIL 21-22, 2015
TUESDAY, APRIL 21
7:00 am Registration and Morning Coffee
INHIBITOR STRATEGIES FOR CHRONIC INFLAMMATION
8:00 Chairperson’s Opening RemarksSeng-Lai “Thomas” Tan, Ph.D., Director and Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc
8:10 PI3K delta Inhibitors for the Treatment of SLE Kamal Puri, Ph.D., Associate Director, Research, Gilead Sciences, Inc.Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated and maintained by autoreactive T and B cells. PI3Kdelta controls many essential B and T cell functions its activity is enhanced in SLE patient lymphocytes. Emerging preclinical data suggests therapeutic potential of PI3Kdelta inhibitors in SLE. In MRL/lprmice, PI3Kdelta inhibition ameliorated lupus progression, reduced the excessive numbers of T effector cells and B cells, decreased cytokine levels and the number of macrophages infiltrating the kidney
8:40 Targeting Protein Tyrosine Phosphatase Sigma for Rheumatoid Arthritis TherapyNunzio Bottini, M.D., Ph.D., Associate Professor, Division of Cell Biology, La Jolla Institute for Allergy and ImmunologyIn the most common form of autoimmune arthritis, rheumatoid arthritis, joints are invaded and destroyed by an inflammatory tissue called pannus- which is composed of immune cells, synoviocytes and neoformed blood vessels. Synovial fibroblasts -a type of synoviocyte that normally lines the inner part of the joint- are a major pannus component and invade and destroy cartilage and bone in rheumatoid arthritis. Elucidation of arthritis-relevant intracellular signaling pathways in synovial fibroblasts is necessary in order to identify targets for novel therapeutic interventions for rheumatoid arthritis patients. This talk will be focused on control of synovial fibroblast signaling by tyrosine phosphatases. In particular we will discuss the role of PTPRS, a tyrosine phosphatase that is regulated by the interaction of its extracellular domain with proteoglycans –an abundant component of joint extracellular matrix and the synovial fluid. We will show that PTPRS regulates synovial fibroblast invasiveness through a mechanism that can be harnessed therapeutically for development of novel anti-rheumatic approaches.
9:10 Phenotyping Blood Polypharmacology via Eicosanoid Profiling of BloodJiao Song, Ph.D., Scientist, Discovery Sciences, Janssen R&DAn effective approach to explore drug pharmacology is to profile metabolic changes in response to pharmacological stimuli. We have developed a molecular phenotyping platform by monitoring eicosanoids, the bioactive lipids involved in inflammation and immune modulations, to take “snapshots” of the key metabolic pathways. Our results demonstrated that distinct responses arise from different compounds with the same nominal protein target, allowing visualization of global pharmacology of drugs/individuals with unprecedented resolution, including on- and off-target effects.
9:40 Coffee Break
10:05 Targeting Interferon Regulatory Factor 5 (IRF5) with Cell Penetrating Peptides: Structure-Based Design and Characterization of Novel Tools for Direct Assessment of IRF5 FunctionSeng-Lai “Thomas” Tan, Ph.D., Director and Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc.Interferon regulatory factor 5 (IRF5) is a critical downstream effector of Toll-like receptor (TLR)-dependent signaling. We report the identification and evaluation of six cell-penetrating peptides (CPPs) designed to disrupt protein-protein interactions considered critical to IRF5 dimerization and/or function. Biochemical studies showed these peptides directly bind IRF5. IRF5 CPPs blocked pro-inflammatory cytokine production in human peripheral blood mononuclear cells stimulated with TLR 7/8 ligand, and IFNa production from plasmacytoid dendritic cells stimulated with TLR9 ligand. Thus, our IRF5 CPPs represent promising tools to probe IRF5 function in vitro and for further development of novel therapeutics against TLR7/8/9-dependent autoimmune diseases.
10:35 Nonimmunosuppressive Cyclophilin Inhibitors as Antiviral and Cytoprotective Agents: the Discovery of Cyclosporines with Improved Pharmaceutical PropertiesJiping FuJiping Fu, Ph.D., Senior Investigator III, Medicinal Chemistry, NovartiChemical modification of the cyclosporine scaffold has led to the discovery of non-immunosuppressive analogs that have potential utility for treating diverse viral infections, inflammatory diseases and mitochondrial disorders. We have prepared new non-immunosuppressive cyclosporine analogs with excellent pharmaceutical and pharmacokinetic properties. This talk will describe the chemical biology of non-immunosuppressive cyclophilin inhibitors, details of our lead optimization effort, and the preclinical profile of the clinical candidate NIM258 for treating HCV infection.
11:05 Novel Small Molecule Immunomodulators that Target Toll-Like Receptors Hang Hubert Yin, Ph.D., Associate Professor, Chemistry and Biochemistry & BioFrontiers Institute, University of Colorado We have developed a novel in silico screening technology, which we applied to target the TLR4/MD-2 complex aiming to identify novel pain management therapy. Experimental results demonstrated that the identified compounds selectively block TLR4 activation both in vitro and in vivo. To demonstrate the general applicability of this methodology, we further developed small-molecule competitive inhibitors of TLRs.
11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
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Inflammation InhibitorsSmall Molecule and Macrocyclic Approaches
SIXTH ANNUAL APRIL 21-22, 2015
1:20 Identification of RORc Inverse Agonists with Favorable in vivo PK and in vivo Suppression of IL-17Benjamin Fauber, Ph.D., Scientist, Small Molecule Drug Discovery, GenentechRORc is a promising target for the treatment of inflammatory disease. Signaling through RORc is critical to the differentiation of pro-inflammatory interleukin-17A+ T helper cells. We identified potent and selective RORc inverse agonists using structure-based drug design principles. Compounds in this series displayed favorable in vivo PK properties and modulated IL-17 in a dose-dependent manner during single dose PK/PD experiments. The improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors.
1:50 Discovery of Novel RORγ γinverse Agonists for Targeting TH17 PathwayJianhua Chao, Ph.D., Associate Director, Medicinal Chemistry, Biogen IdecRORγt is a ligand-regulated transcription factor and is required for the development and function of multiple important pro-inflammatory lymphocyte lineages including TH17 cells. RORγt-expressing cells and the cytokines they produce have been implicated in the pathogenesis of many autoimmune diseases. Disruption of the RORγt /TH17 pathway by small molecule inhibition may provide useful therapeutic intervention. We have explored multiple series of inverse agonists, achieving potent inhibition of the target and with associated acceptable properties for further investigation.
2:20 Animal Models of Ocular Inflammation Sponsored by and Their Translatability to the ClinicClaire M. Gelfman, Ph.D., Senior Director, Preclinical and Translational Services, Ophthalmology, Ora, Inc.Achieving proof-of-concept in animal models of ophthalmic disease is a commonly desired prerequisite for advancing drugs into the clinic. The decision of the best model for evaluation depends on the disease indication under consideration, as well as the mechanism of action targeted by the therapeutic being tested. In addition, the choice of endpoints for the preclinical studies should mirror, when possible, those that will be evaluated in the clinic. In this presentation, we will review several ocular inflammatory models that recapitulate specific features of ophthalmic disease. Representative data will be presented, as well as validation with clinical comparators, when available. This approach can be applied to the early evaluation of new chemical entities, as well as repurposing of compounds validated in other disease indications. The accumulation of relevant animal model proof of concept data will give leverage to a program and play a critical role in making sound go/no-go decisions early in the development process.
2:35 Refreshment Break in the Exhibit Hall with Poster Viewing
NEW TARGETS, NEW APPROACHES?
»3:20 FEATURED PRESENTATION: Site-Directed Ligand Discovery for PPI and Allosteric Enzymes
Michelle Arkin, Ph.D., Associate Professor, Pharmaceutical Chemistry, University of California, San FranciscoProtein-protein interactions and allosterically regulated enzymes have been challenging but important targets for probe- and drug discovery, especially in the inflammation field. We and others
have found that fragment-based lead discovery can provide chemical starting points and furthermore serve as insightful probes of protein conformation. The Tethering method of fragment discovery links thiol-containing compounds to specific cysteine residues and therefore serves as a site-directed approach to interrogating ‘cryptic’ allosteric sites and protein interfaces.
»3:50 FEATURED PRESENTATION: Allosteric Inhibitors of Interleukin-2-inducible T-cell Kinase (ITK)
Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, PfizerInterleukin-2-inducible T-cell kinase (ITK) is a critical mediator of T cell signaling and hence an attractive target for T-cell mediated inflammatory diseases. We have discovered allosteric Type III inhibitors of ITK that also bind to its ATP site. Through classical medicinal chemistry approaches, we have been successful in further optimization of these compounds that leads to selective inhibition of the inactive form of ITK. We will describe how an integrated biophysical technology platform coupled with classical enzymology studies enabled the discovery of allosteric ITK inhibitors.
Brian K. Shoichet, Ph.D., Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco(please see page 2 for details)
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
WEDNESDAY, APRIL 22
7:30 am Continental Breakfast Breakout DiscussionsIn this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.
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Inflammation InhibitorsSmall Molecule and Macrocyclic Approaches
SIXTH ANNUAL APRIL 21-22, 2015
8:45 Discovery and Design of BTK InhibitorsLongcheng Wang, Ph.D., Scientist III, Medicinal Chemistry, PharmacyclicsPharmacyclics’ ibrutinib (PCI-32765) is a first-in-class small molecule inhibitor for Bruton’s tyrosine kinase (BTK) under Phase III clinical development for B cell malignancies. It binds covalently to Cys481 of BTK and suppresses B cell receptor (BCR) activation of primary B lymphocytes. Ibrutinib’s discovery and some of our recent work for identifying a backup covalent inhibitor for BTK will be discussed.
9:15 Development of a Bruton’s Tyrosine Kinase Inhibitor, ONO-4059: Potential Treatment for Rheumatoid Arthritis & Systemic Lupus ErythematosusYuko Ariza, Ph.D., Associate Project Leader, Exploratory Research Laboratories II, Ono Pharmaceutical Co.ONO-4059 is a highly selective, orally bioavailable inhibitor of Btk and Tec kinase activity with a potency (IC50) of 2.2 and 5.3 nM. Data from the ongoing Phase 1 study in hematology cancer demonstrated a promising efficacy in CLL and NHL with a favorable safety profile. Because ONO-4059 reversibly blocks BCR signaling in B-cells and function in monocyte, mast cell and osteoclasts, we hypothesized that ONO-4059 could be an effective therapy in RA and SLE.
9:45 Coffee Break in the Exhibit Hall with Poster Viewing
10:30 Discovery of a New Series of Small Molecule Bruton’s Tyrosine Kinase InhibitorsMark Sabat, Ph.D., Principal Scientist, Medicinal Chemistry, TakedaBruton’s Tyrosine Kinase (BTK) is a cytoplasmic tyrosine kinase that regulates immunoreceptor signaling pathways. Inhibition of BTK is postulated to be an efficacious therapy for multiple autoimmune diseases. BTK has a high structural similarity with the kinase LCK with only two residue differences
present in the active site. This talk will explain how structural differences between BTK and LCK were exploited to discover a series of highly selective fragment derived candidate molecules.
11:00 PPIP5K 1 and 2: A New Class of Small Molecule Kinases for Anti-Inflammatory Drug DevelopmentHuanchen Wang, Ph.D., Senior Scientist, Signal Transduction, National Institute of Environmental Health Sciences, NIHPPIP5K1/2 are two small molecule kinases that synthesize 1-IP7, an activator of virus-mediated, interferon-beta transcription. When this inflammatory signature persists, it can predispose humans to obesity, diabetes and age-related cognitive decline. PPIP5Ks therefore offer a new anti-inflammatory target. Structural and mutagenic studies have revealed PPIP5Ks utilize a surface-mounted, substrate-capture site that delivers substrate into the catalytic pocket. This “catch-and-pass” reaction mechanism offers a novel means for pharmacological targeting of this enzyme activity.
11:30 TYK2 Inhibitors and Their Role in IL12- and IL23-Pathway SignalingSteven Magnuson, Ph.D., Associate Director, Discovery Chemistry, Genentech, Inc.TYK2 is a member of the family of Janus kinases that are receptor-associated cytoplasmic tyrosine kinases with a central role in cytokine signaling. TYK2 is known to be a key mediator of IL12-and IL23-signaling, thus being implicated in diseases of chronic inflammation. Structure- and property-based optimization of screening hits to highly potent and selective TYK2 inhibitors suitable for in vivo studies will be described.
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Protein-Protein InteractionsTargeting PPIs for Therapeutic Interventions
EIGHTH ANNUAL APRIL 21-22, 2015
TUESDAY, APRIL 21
7:00 am Registration and Morning Coffee
PPIs INVOLVED IN CANCER
8:00 Chairperson’s Opening RemarksEdward R. Zartler, Ph.D., President & CSO, Quantum Tessera Consulting
8:10 Structural and Biophysical Studies of Novel, Potent HDM2-p53 AntagonistsMark McCoy, Ph.D., Research Fellow, Medicinal Chemistry, MerckThe p53 tumor suppressor is normally ubiquitinated and targeted for degradation. HDM2 is a protein responsible for the ubiquitination of p53. Thus antagonists to the complex are thought to stabilize the presence of p53. This presentation will describe work spanning more than 12 years for finding antagonists of the p53/HDM2 complex. The talk will cover fragment screening, HTS hit validation, assay development, X-ray and NMR structure determination.
8:40 Macrocycles that Modulate the C-Terminus of HSP90: A New Mechanism for Inhibiting Protein FoldingShelli McAlpine, Ph.D., Associate Professor, Chemistry, University of New South WalesClassic oncogenic heat shock protein 90 (Hsp90) inhibitors target the N-terminus of the protein, triggering a survival mechanism in cancer cells referred to as the heat shock response (HSR). Inhibiting Hsp90 by modulating the C-terminus does not trigger a HSR, making it a highly attractive chemotherapeutic approach. Our compounds are the first to effectively inhibit hsp90’s function, without triggering a cell protection mechanism.
9:10 Assessing Flexibility and Druggability Sponsored by
of PPIs Using Molecular DynamicsSoumya Ray, Ph.D., Senior Scientist, Applications Science, SchrödingerProtein-protein interactions (PPIs) are promising drug targets for modulating biological pathways. We present computational approaches for studying and targeting PPI interfaces with small-molecule inhibitors. We first explore PPIs with molecular dynamics and assess druggability of different conformational states; then, we study the thermodynamics of water molecules at PPI interfaces to detect binding hotspots. Finally, we use mixed solvent molecular dynamics to induce druggable pockets in PPIs. These studies show that computational approaches can offer insights into and facilitate inhibitor design for PPIs.
9:40 Coffee Break
10:05 Hit-to-Lead Optimization of Palm Site Binders as Selective Inhibitors of USP7Chudi Ndubaku, Ph.D., Senior Scientist, Discovery Chemistry, GenentechDysregulation of the ubiquitin proteasome system (UPS) has been associated with disease pathogenesis, including several types of cancer. In particular, ubiquitin-specific protease 7 (USP7) has been shown to be a critical regulator of p53. Using fragment-based screening by SPR and NMR, we derived leads that were shown, by X-ray crystallography, to bind to the catalytic domain of USP7 within the Palm region. We will present our lead identification
efforts including structural biology information that were crucial for compound optimization.
10:35 Design and Synthesis of a New Sponsored by Generation of Protein-Protein Interaction InhibitorsRoman Kombarov, Ph.D., Head, Business Development, Asinex CorporationProtein-Protein interactions (PPI) have great potential as therapeutic targets but are currently one of the most challenging areas in drug discovery partly due to specific structural features of PPI modulating ligands. This talk will focus on the lessons Asinex has learned and its unique approach to address the problem using a “compound-to-target” strategy, our design of lead like PPI ligands, and lead optimization strategy. We will also briefly introduce a case study in PPI drug discovery.
11:05 The Challenges of Targeting Protein-Protein Interactions in Ras-SOS Using FragmentsJoe Patel, Ph.D., FBLG Specialist, Discovery Sciences, AstraZenecaConstitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase activating protein-catalysed mechanisms, and perpetual activation of Ras pathways. A fragment screening campaign using X-ray crystallography led to the discovery of three fragment binding sites on the Ras:SOS complex. Identification of tool compounds binding at each of these sites allowed exploration of new approaches to Ras pathway inhibition by stabilising or covalently modifying the Ras:SOS complex.
11:35 A Systematic Approach for Developing Orthosteric Inhibitors of PPIs: Application to Ras/Sos Inhibitor DesignParamjit Arora, Ph.D., Professor, Department of Chemistry, New York UniversityProteins often utilize small folded domains for interactions with other proteins. The basic hypothesis guiding our research is that by mimicking these domains we can modulate the function of a particular protein-protein interaction with metabolically stable synthetic molecules. This presentation will discuss synthetic approaches to develop protein domain mimics as modulators of intracellular protein-protein interactions, with the Ras-Sos interaction as a case study.
12:05 pm Luncheon Presentation: Designing Sponsored by Inhibitors for Protein-Protein Interactions– Challenges and ApproachesPhillip Black, Ph.D., Senior Scientist, Discovery Services, Charles RiverDesigning and synthesizing molecules tailored to the biological target or family of interest is key to enhancing hit rates and optimizing early discovery. For over 15 years, BioFocus has met this demand with its ongoing development of SoftFocus® libraries of novel compounds that have aided core area research in kinases, GPCRs and ion channels. Our discussion will highlight our history of success and review our continued strategies to tackle today’s challenging and emerging targets.
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Protein-Protein InteractionsTargeting PPIs for Therapeutic Interventions
EIGHTH ANNUAL APRIL 21-22, 2015
1:20 Novel Tetra-Ubiquitin Substrates of Sponsored by
Different Linkages for more Biologically Relevant Deubiquitinylase Assays Utilizing AlphaLISA TechnologyDaniel Cardillo, MSc, Application Scientist, Global Discovery Applications, PerkinElmer
1:35 Homology Models of the HIV-1 Attachment Inhibitor BMS-626529 Bound to GP120 Suggest a Unique Mechanism of ActionDavid Langley, Ph.D., Senior Scientist, Computational Chemistry, Bristol-Myers Squibb Co.
2:05 Non-Catalytic Site Integrase Inhibitors: Interrogating a PPI Target via Virtual and Fragment ScreeningDoug C. Beshore, Ph.D., Project Leader, Exploratory Chemistry, Merck Research LaboratoriesThe quest for novel mechanisms for the treatment of HIV remains a world-wide public health objective. An emerging mechanism is centered around the disruption of the lens epithelial growth factor (LEDGF/p75)-HIV Integrase (IN) interaction, which has been shown to inhibit viral replication. Targeting this protein-protein interaction with small molecules (LEDGINs) that binds to the LEDGF/p75 binding pocket of IN via virtual and fragment-based strategies will be presented.
2:35 Refreshment Break in the Exhibit Hall with Poster Viewing
NEW TARGETS, NEW APPROACHES?
»3:20 FEATURED PRESENTATION: Site-Directed Ligand Discovery for PPI and Allosteric Enzymes
Michelle Arkin, Ph.D., Associate Professor, Pharmaceutical Chemistry, University of California, San FranciscoProtein-protein interactions and allosterically regulated enzymes have been challenging but important targets for probe- and drug discovery, especially in the inflammation field. We and others have found that fragment-based lead discovery can provide
chemical starting points and furthermore serve as insightful probes of protein conformation. The Tethering method of fragment discovery links thiol-containing compounds to specific cysteine residues and therefore serves as a site-directed approach to interrogating ‘cryptic’ allosteric sites and protein interfaces.
»3:50 FEATURED PRESENTATION: Allosteric Inhibitors of Interleukin-2-inducible T-cell Kinase (ITK)
Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, PfizerInterleukin-2-inducible T-cell kinase (ITK) is a critical mediator of T cell signaling and hence an attractive target for T-cell mediated inflammatory diseases. We have discovered allosteric Type III inhibitors of ITK that also bind to its ATP site. Through classical medicinal chemistry approaches, we have been successful in further optimization of these compounds that leads to selective inhibition of the inactive form of ITK. We will describe how an integrated biophysical technology platform coupled with classical enzymology studies enabled the discovery of allosteric ITK inhibitors.
Brian K. Shoichet, Ph.D., Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco(please see page 2 for details)
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
WEDNESDAY, APRIL 22
7:30 am Continental Breakfast Breakout Discussions
TARGETING DNA BINDING PROTEINS
8:40 Chairperson’s RemarksMichelle Arkin, Ph.D., Associate Professor, Pharmaceutical Chemistry, University of California, San Francisco
8:45 Development of Small Molecule Inhibitors of Epstein-Barr Virus-Associated DiseasesTroy Messick, Ph.D., Staff Scientist,Virology,TheWistar InstituteEBV is a DNA tumor virus that causes 1-2% of human cancers. Our therapeutic approach targets EBNA1, a multifunctional protein critical for viral replication and genome maintenance. We used a fragment-based approach to develop a small molecule lead series that selectively inhibits the DNA-binding activity of EBNA1, has activity in cell based assays, and provides tumor growth inhibition in xenograft studies. These data establish proof-of-concept for targeting EBNA1—a protein previously thought to be undruggable.
9:15 Targeting the NPM1 and FOXM1 Interaction as a Novel Anticancer Therapy Andrei Gartel, Ph.D., Associate Professor, Medicine, University of Illinois, Chicago Targeting FOXM1, a transcription factor whose gene is one of the most over-expressed in liver cancer, in mono- or combination therapy has shown promising therapeutic benefits in current research. We found, via mass spectrometric analysis, that FOXM1 interacts with the chaperone, nucleophosmin (NPM1), which is ubiquitously expressed in mammalian cells. FOXM1- NPM1 interaction is also required for sustaining the level and localization of FOXM1. We report the first NPM1 peptide that inhibits FOXM1 in cancer cells, paving the way to develop specific FOXM1 inhibitors.
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9:45 Coffee Break in the Exhibit Hall with Poster Viewing
BCL PROTEINS AND PARTNERS
10:30 Targeting MCL1 for the Treatment of CancerMichael H. Serrano-Wu, Ph.D., Director, Medicinal Chemistry, Center for the Development of Therapeutics, Broad InstituteMCL1 is highly expressed in many tumor types and high expression levels of MCL1 contribute to tumor development and resistance to chemotherapy. Recently we discovered that the top biomarker for MCL1 dependency is the low expression levels of BCL-xL, and high expression levels of BCL-xL predicted resistance to MCL1 modulation. Here, we describe our multi-prong strategy towards discovering selective MCL1 inhibitors which includes direct-binding and cellular assays for complementary molecular approaches to targeting diverse aspects of MCL1 biology.
11:00 Discovery and Structure-Based Optimization of Novel Small Molecule Mcl-1 InhibitorsZaneta Nikolovska-Coleska, Ph.D., Assistant Professor, Pathology, University of Michigan Medical SchoolThis talk presents our HTS identification and subsequent structure-based optimization of inhibitors of the interactions between Mcl1 and pro-apoptotic proteins. With our small-molecule inhibitor, we validated Mcl-1 as a potential
therapeutic target for pancreatic cancer (Mol Cancer Ther, 2014) and furthermore demonstrate that Mcl-1 inhibitors can act as radiosensitizers in pancreatic cancer by inducing apoptosis (Neoplasia, under revision). Furthermore, using model cell lines dependent upon specific anti-apoptotic BCL-2 family members, we have shown the on target effects of our selective Mcl-1 inhibitors.
11:30 Modulators of PUMA: BCL2 Interactions Discovered Using High-Throughput BRET2 and Mammalian-2-Hybrid AssaysMary Ellen Digan, Ph.D., Senior Research Investigator I, Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Inc.PUMA is a key initiator of DNA-damage-induced mitochondrial apoptosis which acts by neutralizing all five anti-apoptotic BCL2 family members via protein-protein interactions mediated by its BH3-domain. Inhibitors of PUMA-induced apoptosis have been proposed as treatments for therapy-induced oral and intestinal mucositis in patients with p53-mutated tumors. This presentation, the first oral disclosure of the use of mammalian-two-hybrid assays in high throughput screening mode, describes an entirely cell-based hit prosecution process based on a BRET2 screen. Full-length proteins were used and we maintained their native mitochondrial location and stayed close to their endogenous protein levels.
12:00 pm Close of Track
Protein-Protein InteractionsTargeting PPIs for Therapeutic Interventions
EMERGING STRATEGIES FOR DISCOVERY OF BROMODOMAIN INHIBITORS
8:00 Chairperson’s Opening Remarks
»8:10 FEATURED PRESENTATION: A Bump-and-Hole Approach to Engineer Controlled Selectivity of BET Bromodomain Chemical Probes
Alessio Ciulli, Ph.D., Reader, Chemical & Structural Biology, BBSRC David Phillips Fellow, College of Life Sciences, University of DundeeWe developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine
mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in disease, and aid association of the pharmacology of BET bromodomain inhibitors to particular targets.
8:40 In silico Discovery and Experimental Validation of Selective Bromodomain InhibitorsAmedeo Caflisch, Ph.D., Professor and Chair, Computational Structural Biology, Department of Biochemistry, University of ZurichWe have discovered in silico, validated by X-ray crystallography, and optimized by chemical synthesis a series of nM potent and selective ligands of the CREBBP bromodomain. Fragment-based, high-throughput docking was employed for the identification of novel scaffolds whose affinity was enhanced. The specificity and easy synthetic availability of our compounds will be useful to unravel the biological role(s) that CREBBP plays. Using the same approach, we have recently identified potent inhibitors of representatives of five different families of bromodomains.
9:10 Using Biophysics to Target Methyl Sponsored by Transferases (HKMTs) with Small MoleculesGregg Siegal, Ph.D., CEO, ZoBioHKMTs are an important class of targets, yet it has proven challenging to develop drug-like inhibitors against them. We have used our TINS NMR technology to screen a diversity fragment collection which has lead to SPR validated, novel hit matter against for 4 HKMTs. The hits target both the SAM and substrate sites. We find differences in the small molecule binding of the HKMTs. This allows us to 1) prioritize HKMTs on ligandability, 2) redefine family relationships based on pharmacology and 3) select specific or pan-family ligands as starting points for drug development efforts.
9:40 Coffee Break
ADVANCES IN BET BROMODOMAIN INHIBITOR DEVELOPMENT
10:05 Discovery of Dual PI3K/BRD4 InhibitorsDonald Durden, M.D., Ph.D., Professor, Vice Chair, Pediatrics, University of California, San Diego School of Medicine; CEO and President, SignalRx PharmaceuticalsA novel thienopyranone molecular scaffold has been discovered to selectively inhibit PI3 kinase as well as the bromodomain protein BRD4. Molecular modeling studies will be presented to describe how these single small molecules can bind to inhibit such distinctly different proteins and their functions. As a cancer therapeutic this dual inhibition mechanism allows for a unique and powerful way to modulate critical components of cancer cells. Key in vitro and animal proof-of-concept efficacy studies will be presented for the lead compound SF2523.
10:35 Discovery and Development of a Potent Dual TRIM24/BRPF1 Bromodomain Inhibitor, IACS-9571, Using Structure-Based Drug DesignWylie Palmer, Ph.D., Institute Research Scientist, Institute of Applied Cancer Science, MD Anderson Cancer CenterWe have developed a potent cellular dual TRIM24/BRPF1 bromodomain inhibitor which will be useful for interrogating the biological role of the bromodomains of these two proteins. We employed three different approaches for finding a starting point, including; virtual screening, assembling an acetyl-lysine mimetic library, and an HTS screen which led to the identification of a lead series. Iterative use of X-ray crystallography and observation of an unexpected binding-mode guided further optimization of this series towards single-digit nM potencies.
11:05 Translating Chromatin Biology into Drug DiscoveryAlex Taylor, Ph.D., Senior Scientist, Medicinal Chemistry, Constellation PharmaceuticalsThere continues to be considerable interest in drugging epigenetic targets due to the profound potential to have an impact on disease. Constellation is interested in the readers, writers and erasers of histone modifications. Our drug discovery efforts towards identifying inhibitors of these therapeutic targets will be discussed.
11:35 Homogeneous Quantitative Biochemical Sponsored by Assay Platform Enabling Discovery and Optimization of Inhibitors for Diverse Therapeutic TargetsDaniel Treiber, Ph.D., Vice President & Site Head, KINOMEscan, DiscoveRx CorporationIt is well established that ligand binding protects proteins from thermal denaturation; however, the broad application of this concept to high-throughput screening has been hindered by a lack of facile HTS-compatible protocols and sensitive, quantitative and precise readout methodologies. Here we describe a novel denaturation-based method that overcomes limitations of current denaturation-based screening methods, in addition to providing benefits over standard non-denaturation-based screening methods. Data generated using this format to query bromodomains, kinases, and more shall be presented.
CHEMICALLY MODULATING DNA & HISTONE METHYLTRANSFERASES
1:15 Chairperson’s RemarksBrian Lohse, Ph.D., Associate Professor, Drug Design and Pharmacology, University of Copenhagen
1:20 Discovery of EPZ015666: A First-In-Class PRMT5 Inhibitor with Potent In Vitro and In Vivo ActivityKenneth W. Duncan, Ph.D., Associate Director, Molecular Discovery, EpizymeWe describe the identification and characterization of EPZ015666 (GSK3235025), a potent, selective and orally available inhibitor of Protein Arginine Methyltransferase-5 (PRMT5). This novel inhibitor is SAM-uncompetitive, peptide-competitive and interacts with the PRMT5:MEP50 complex through a unique inhibition mode not previously observed for any SAM-dependent enzyme. Treatment with EPZ015666 on Mantle Cell Lymphoma (MCL) cells leads to inhibition of PRMT5 mediated methylation and cell killing. Robust activity was also observed upon oral dosing of EPZ015666 in multiple MCL xenografts.
1:50 Discovery of a Potent and Specific Drug to Inhibit PRMT5 in Hematologic and Solid TumorsChenglong Li, Ph.D., Associate Professor, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Comprehensive Cancer CenterThrough our lab-developed novel fragment-based drug design strategy, MLSD (multiple ligand simultaneous docking), we have optimized a class of drug-like small molecules in three iterative rounds. These PRMT5 inhibitors are potent and specific with favorable PK/PD properties. This presentation will discuss a novel lead in this series on the design process and demonstrate its efficacies in various hematologic and solid tumor models, such as lymphoma, AML and high grade astrocytomas.
2:35 Refreshment Break in the Exhibit Hall with Poster Viewing
3:20 Discovery of First-in-Class Reversible Dual Inhibitors of DNA Methyltransferase and Histone Methyltransferase G9aJulen Oyarzabal, Ph.D., Director, Translational Sciences, Center for Applied Medical Research (CIMA), University of NavarraWe have designed and synthesized a new series of small molecules that act as potent, selective and reversible DNMT and G9a inhibitors. The most potent molecules inhibit both targets in the nanomolar range (IC50<100nM) and their functional responses, in vitro cellular, clearly show the corresponding impact on their epigenetic marks (2meH3K9 and 5-methylcytosine) with EC50 values of around 100nM, thus, confirming their mode of action. Off-target profiling shows that these molecules are selective against a panel of 37 additional epigenetic targets (<50% inhibition at 10mM).
3:50 The Discovery and Characterization of A-366, a Potent and Selective Inhibitor of Histone Methyltransferase G9aRamzi Sweis, Ph.D., Research Investigator, Discovery Chemistry, AbbVie, Inc.
This talk highlights the discovery of a new class of inhibitors for G9a that are among the most potent and selective known for this methyltransferase. Physical and biological characterization of A-366, a representative compound from this class of inhibitors, has highlighted the utility of using this compound as a probe for studying G9a function. Further characterization has demonstrated efficacy of A-366 in particular models of leukemia.
Brian K. Shoichet, Ph.D., Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco(please see page 2 for details)
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
WEDNESDAY, APRIL 22
7:30 am Continental Breakfast Breakout DiscussionsIn this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.
CHEMICALLY MODULATING HISTONE DEMETHYLASES
8:40 Chairperson’s RemarksKaren Maegley, Ph.D., Associate Research Fellow, Integrative Biology and Biochemistry, Pfizer Oncology
8:45 Overcoming Drug Resistance through Small Molecule Epigenetic ModulationElisabeth Martinez, Ph.D., Assistant Professor, Pharmacology, University of Texas Southwestern Medical CenterRecent results will be described that establish the use of epigenetic inhibitors to overcome the transcriptional reprogramming that facilitates drug resistant phenotypes.
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9:15 Epigenetic Inhibitors are Potentially Useful Therapeutics for Acute LeukemiaYongcheng Song, Ph.D., Associate Professor, Pharmacology, Baylor College of MedicineWe synthesized several potent LSD1 inhibitors and found they exhibited strong activity against MLL-rearranged leukemia cells, while these compounds are non-cytotoxic to several other tumor cells. One compound showed significant in vivo activity in a systemic leukemia mouse model without overt toxicities. The mechanistic studies of LSD1 inhibitors as well as their synergy with other epigenetic compounds against MLL leukemia are discussed.
9:45 Coffee Break in the Exhibit Hall with Poster Viewing
TOOLS AND STRATEGIES ENABLING EPIGENETIC DRUG DISCOVERY
10:30 Histone Binding Mechanisms and Specificities of PHD FingersTatiana Kutateladze, Ph.D., Professor, Department of Pharmacology, Anschutz Medical Campus, University of ColoradoPlant homeodomain (PHD) fingers comprise one of the largest families of epigenetic effectors capable of recognizing PTMs (posttranslational modifications) of histones. Here, I summarize the structures and binding mechanisms of the PHD fingers that select for modified and unmodified histone H3 tails. I will compare the specificities of PHD fingers, Tudor and other histone readers, and discuss the significance of crosstalk between PTMs and the consequence of combinatorial readout for the selective recruitment of these effectors to chromatin.
11:00 Discovery of Novel Small Molecules and Small Cyclic Peptides as Chemical Tools and Inhibitors, Using DNA Encoded Peptide Libraries for HDMs and HMTsBrian Lohse, Ph.D., Associate Professor, Drug Design and Pharmacology, University of CopenhagenEpiDiscoverY has previously shown new strategies and is continuously searching for alternative ways to identify new tool compounds for epigenetic targets, primarily HDMs (KDM4 and KDM1) and HMTs (EHMT and PRMTs). Here we present how we have used DNA encoded peptide libraries to identify both small molecule inhibitors and recently small cyclic peptide inhibitors for KDM4 and KDM1 and for EHMT and PRMTs. The entire strategy and timeline is presented along with two new assays.
11:30 Mechanistic Characterization of PRMT5 Enzyme ComplexesKaren Maegley, Ph.D., Associate Research Fellow, Integrative Biology and Biochemistry, Pfizer OncologyPRMT5 methylates arginine residues on protein substrates. Many different PRMT5 complexes have been described and different complexes are suggested to have different substrate preferences. We have enzymatically characterized PRMT5 complexes and will compare and contrast mechanism of action and inhibition and suggest a potential regulation mechanism.
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Kinase Inhibitor ChemistryShaping Current and Future Development of Kinase Inhibitors
SIXTH ANNUAL APRIL 22-23, 2015
WEDNESDAY, APRIL 22
12:30 pm Registration
TRENDS IN KINASE INHIBITOR DISCOVERY AND DEVELOPMENT
1:30 Chairperson’s RemarksRogier C. Buijsman, Ph.D., Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)
1:40 Drug Discovery Considerations in the Development of Covalent InhibitorsGerald Lelais, Ph.D., Senior Research Investigator, Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation (GNF)In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This presentation will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.
2:10 The Discovery of LY2606368, a Potent and Selective Inhibitor of Chk1 and Chk2 and Its Use as a Treatment for CancerDavid Barda, Ph.D., Research Advisor, Discovery Chemistry Research and Technologies, Eli Lilly and CompanyThe role of Chk1 as a regulator of cell cycle DNA damage checkpoints has been well described. Our discovery of LY2606368 helped to uncover the additional Chk1-mediated catastrophic effects early in DNA replication resulting in double stranded DNA cleavage. Replication effects coupled with inhibition of checkpoint mechanisms delivers a dual mechanism efficacy through a single biological target. We will detail the discovery through pharmacophore modeling and structure based design as well as the preclinical results achieved with this novel agent.
2:40 New Prototypes of AGC Kinase InhibitorsOliver Plettenburg, Ph.D., Head, Biosensors & Chemical Probes, R&D, Sanofi-Aventis
3:10 Binding Studies of Type I and Type II Sponsored by Kinase Inhibitors against Bcr-Abl Kinase Using Back-Scattering Interferometry Scot R. Weinberger, Executive Vice President, Molecular Sensing Inc.The binding affinity of Type I, and Type II Bcr-Abl kinase inhibitors with wild type and four mutant Bcr-Abl kinases were measured using Back-Scattering Interferometry (BSI). BSI successfully demonstrated facile determination of Kd for all systems, with a high degree of concordance with IC50. These results indicate that BSI binding studies both class I and II kinase inhibitors can easily be performed, allowing for confirmation of target engagement as well as direct binding assessment of kinase inhibitors against inactive Bcr-Abl kinase.
3:40 Celebratory 10th Annual Refreshment Break in the Exhibit Hall with Poster Viewing
4:20 Next-Generation Kinase Panel Screening Measuring Target Residence Time and Kinetic SelectivityRogier C. Buijsman, Ph.D., Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)Selective kinase inhibitors are optimized for increased target residence time and profiled on large panels of biochemical and cell-based assays. Genotypic, phenotypic and pathway information are combined to determine the optimal compound for a particular patient responder population. This presentation will discuss an in-depth knowledge concerning the relationship between cellular and biochemical profiles of marketed kinase inhibitors as well as insight in genetic susceptibility of these inhibitors.
4:50 Novel Kinase Inhibitor Design Paradigms: The Hydrophobic Spine and the Discovery of SlownessGerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BVTo improve the correlation between biochemical and cellular or in vivo efficacy, it is advantageous to optimize the residence time of compound-target complexes early in the drug discovery process. In this presentation the prospective engineering of binding kinetic signatures into inhibitors that exhibit slow koff by applying “deep-pocket-directed” scaffolds is exemplified. Details of the applied “retro-design” approach for novel kinase inhibitors that disrupt the hydrophobic spine will be highlighted by a lead finding campaign that yielded novel, selective, and highly efficacious CDK-8 inhibitors.
5:20 Breakout DiscussionsIn this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.
6:20 Close of Day
6:30 Dinner Short Courses**Separate registration required; please see page 4 for details
“Up-to-date discussion on late breaking strategies for novel kinase inhibitor design.”
10:15 CASE STUDY: Discovery of ABL001: A New Allosteric Inhibitor of BCR-ABLAndreas Marzinzik, Ph.D., Director, Lead Generation Chemistry, Novartis Institutes for BioMedical ResearchABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action which recently entered Phase I development for the treatment of patients with chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL).
10:45 CASE STUDY: Enzyme Activators: Targeting AMP-Activated Protein Kinase (AMPK)Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, PfizerIn recent years, AMPK has emerged as a desirable target for modulation of numerous diseases, yet clinical therapies remain elusive. We provide the full-length structure of the widely expressed α1β1γ1 isoform of mammalian AMPK, along with detailed kinetic and biophysical characterization. We characterize binding of the broadly studied synthetic activator A769662 and its analogs. Our studies follow on the heels of the recent disclosure of the α2β1γ1 structure and provide insight into the distinct molecular mechanisms of AMPK regulation by AMP and A769662.
11:15 Testing, Testing, MASS-1, Two...Testing. Sponsored by
David Myszka, CEO, Biosensor Tools LLCIs this thing on? Sierra Sensor’s MASS-1 is a label-free biosensor platform that can do everything we’ve come to expect from biosensor systems, including characterizing protein/protein, antibody/antigen, and small molecule/target interactions. But, its unique configuration of eight
parallel flow channels expands the MASS-1’s throughput and versatility. For example, in drug discovery we can test fragment libraries faster. Or we can test compounds against more targets at the same time to identify specific binders – you’d be surprised how many compounds bind all over proteins. In addition, the MASS-1’s internal referencing and fast data collection rate make it possible to extract more kinetic information when testing weak binders. Together, these features help advance the state-of-the-art of molecular interaction analysis and everyone should like that.
11:30 Dynamics-Based Allostery in Protein KinasesAlexandr P. Kornev, Ph.D., Project Scientist, Department of Pharmacology, University of California, San DiegoTo understand the nature of allosteric signaling in protein kinases we studied microsecond-scale molecular dynamics simulations of protein kinase A. The observed community maps were sensitive to the presence of different ligands and provide a new framework for interpreting long-distance allosteric signaling. Communication between different communities was also in agreement with the previously defined architecture of the protein kinase core based on the “hydrophobic spine” network. This allows us to suggest that community analysis can be used for other protein kinases.
12:00 pm Non-ATP Competitive Inhibitors are Selective for PLK1 and Target Tumors Resistant to Catalytic Site CompoundsCampbell McInnes, Ph.D., Associate Professor, Drug Discovery and Biomedical Sciences, University of South CarolinaWe have developed and validated REPLACE as a general strategy for protein-protein interactions in the development of non-ATP competitive inhibitors of protein kinase oncology targets including in the first instance, cyclin dependent kinases through the substrate recruitment site. REPLACE has been extensively validated through application to the Polo-Box domain of PLK1 to generate selective compounds that are potent in cell culture cancer models, have cellular phenotypes consistent with inhibition and which are active against a mutant form of the kinase resistant to clinically used inhibitors.
12:30 Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing) and Poster Awards
1:45 Structure- and Property-Based Design and in vivo Profiling of Potent and Selective Tetrahydroindazole ITK InhibitorsZhonghua Pei, Ph.D., Senior Scientist and Project Team Leader, Discovery Chemistry, GenentechInhibitors of interleukin-2 inducible T cell kinase (ITK) in T cell signaling, has been pursued as a potential treatment for immune diseases such as allergic asthma. Through scaffold-hopping of the original high-throughput screen (HTS) hits of indazoles, we discovered tetrahydroindazoles (THIs) as an advanced lead series. Using structure- and property-based design, we were
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Kinase Inhibitor ChemistryShaping Current and Future Development of Kinase Inhibitors
SIXTH ANNUAL APRIL 22-23, 2015
able to optimize multiple properties of THIs simultaneously: potency, kinase selectivity, solubility and cytotoxicity. The optimized inhibitors demonstrate excellent in vitro cellular potency and in vivo PD marker modulation.
2:15 Discovery of Substituted Aminopyridine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)Snahel Patel, Scientific Manager, Discovery Chemistry, Genentech, Inc.Neurodegenerative diseases such as Alzheimer’s and Parkinson’s represent significant unmet medical needs with no therapies able to slow the course of disease. Dual Leucine Zipper Kinase (DLK) is a neuronal specific upstream regulator of the JNK pathway that was recently identified as a central regulator of degeneration in multiple contexts. Starting from a high-throughput screening hit, we have developed potent, selective and brain penetrant DLK specific inhibitors that display activity in neurodegeneration models.
2:45 Refreshment Break
3:00 Nanocyclix Approach towards Unexplored Kinases: Identification of RIP2 and SIK2 Inhibitors for Application in Auto-Immune and CNS DisordersJan Hoflack, Ph.D., CSO, Oncodesign BiotechnologyOncodesign’s chemical biology approach using its macrocyclic chemistry platform has allowed the identification of potent and selective inhibitors for RIP2 and SIK2 kinases. The molecules have been used as chemical probes to validate the potential of these novel targets. Data will be presented that demonstrate the potential role of RIP2 as a target of interest in auto-immune diseases and for SIK2 in neuroprotection/ageing. The discovery and optimization of the inhibitors will be presented.
3:30 PF-06463922, a Novel Small Molecule Inhibitor of ALK/ROS1 with Preclinical Brain Availability and Broad Spectrum Potency against ALK-Resistant MutationsTed W. Johnson, Ph.D., Research Fellow, Medicinal Chemistry, Pfizer OncologyPF-06463922, a novel macrocyclic inhibitor of ALK/ROS1, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutants representing all of the patient crizotinib resistant mutations reported to date. Successful optimization of molecular weight and lipophilic efficiency leveraging structure-based drug design techniques led to ligands with overlapping broad spectrum potency, low transporter efflux, and brain penetration. PF-06463922 is currently in Phase 1/2 clinical trials.
4:00 Discovery of SB1578 - A JAK2 Small Molecule Macrocycle for Autoimmune DiseasesAnthony D. William, Ph.D., Senior Scientist, The Agency for Science, Technology and Research (A*STAR)-ICESSB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also demonstrates potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. Herein the design and optimization of the macrocyclic Jak2/Flt3 inhibitor will be discussed including the biochemical and cellular activities of SB1578 that translate into its high efficacy in rodent models of arthritis.
»1:40 FEATURED SPEAKER: Understanding Permeability of Peptide and Peptidomimetic Macrocycles
Spiros Liras, Ph.D., Vice President, Worldwide Medicinal Chemistry, CVMED, PfizerPeptidic macrocycles represent a potential lead option for difficult drug targets including protein-protein interaction inhibitors and class B GPCRs. As part of a network with leading researchers in academia we set out to develop principles for the rational
design of permeable and orally bioavailable macrocycles. We have developed strategies for the generation of orally bioavailable peptidic macrocycles which include N-methylation, hydrophobic shielding of polar functionality, hydrogen bond donor management with intramolecular hydrogen bond networks and incorporation of peptidomimetic fragments. Application of these design strategies in case studies, identification of key limitations and future opportunities for this modality will be discussed in this presentation.
2:10 Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical CandidatesJan Kihlberg, Ph.D., Professor, Department of Chemistry, BMC, Uppsala University, SwedenAnalysis of a comprehensive set of drugs and clinical candidates having MW >500 Da demonstrate significant opportunities for discovery of cell permeable and orally bioavailable drugs in physicochemical space far beyond the rule of 5 (bRo5). As compared to Ro5 compliant drugs, those bRo5 may modulate different kinds of targets, in particular ones having flat and groove shaped binding sites. Interestingly, macrocycles appear to have features that provide special opportunities in bRo5 drug space.
2:40 Towards Design Rules for MacrocyclesAdrian Whitty, Ph.D., Department of Chemistry, Biomolecular Engineering Research Center, Boston UniversityThe potential utility of synthetic macrocycles as drugs, particularly against challenging targets such as protein-protein interactions, has been widely discussed. We have analyzed the binding modes of a representative set of macrocycle-protein complexes. The results allow us to propose specific guidelines for the design of synthetic macrocycles libraries possessing structural and physicochemical features likely to favor strong binding to protein targets and also good bioavailability.
3:10 Approaching Macrocyclic Chemical Space Sponsored by
Through Non-Conventional RoutesScott Breinin, Ph.D., Senior Medicinal Chemist, Medicinal Chemistry, Asinex CorporationAt Asinex, over a 5 year period of macrocyclic synthetic development, we have learned many lessons, developed new approaches, and also created a platform that uses macrocycles as the core element in the design of novel peptidomimetic molecules. These structures have the correct geometry and substitution characteristics to align the requisite functional groups in three dimensions and are thus able to disrupt key elements of the PPI interface. This talk will focus on how this strategy addresses an unmet need in drug discovery. We will also touch on lessons learned in our history of macrocyclic development.
3:40 Celebratory 10th Annual Refreshment Break in the Exhibit Hall with Poster Viewing
4:20 Constrained Cyclic Peptides: Conformation vs. BioavailabilityDavid P. Fairlie, Ph.D., Professor and Head, Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of QueenslandWe live in a new age of injectable peptide drugs. Exponential growth in protein/peptide therapeutics will continue due to the increasing need to target larger, shallower, interacting protein surfaces. To achieve potency and high selectivity, larger molecules with additional chemical foliage are required. Cyclic peptides provide opportunities to increase molecular size and interactions, while constraining ligands into pre-organized protein-binding conformations. What limits the conversion of cyclic peptides into potent, selective and orally bioavailable drugs?
4:50 Structural Basis of Macrocycle-Enzyme InteractionMarkus Seeliger, Ph.D., Assistant Professor, Pharmacological Sciences, Stony Brook UniversityWe have determined the co-crystal structures of unusually specific macrocyclic inhibitors of protein kinases and proteases. These macrocycles were derived from a DNA-templated library of macrocycles. Currently, there are few synthetic macrocycles in clinical use. In fact, there is only a small number of protein co-crystal structures with macrocyclic compounds. Our recently published co-crystal structures of Src and IDE in complex with macrocyclic inhibitors gives new insights into the way these compounds achieve specificity.
5:20 Breakout DiscussionsIn this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.
6:20 Close of Day
6:30 Dinner Short Courses**Separate registration required; please see page 4 for details
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Macrocyclics and Constrained PeptidesBigger, Better, But Hopefully Still Oral, Small Molecules
THIRD ANNUAL APRIL 22-23, 2015
THURSDAY, APRIL 23
8:00 am Morning Coffee
»8:30 PLENARY KEYNOTE PRESENTATION: Fragment-Based Drug Discovery: A Fifteen Year (Re-)Evolution
Harren Jhoti, Ph.D., President & CEO, Astex Pharmaceuticals(please see page 2 for details)
9:30 Coffee Break in the Exhibit Hall with Poster Viewing
CASE STUDIES: PROGRESSING IN THE DEVELOPMENT PIPELINE
10:10 Chairperson’s Remarks
10:15 Exploring Macrocycles for Protein-Protein Interaction Targets: the Discovery of Novel Bifunctional XIAP AntagonistsNicholas Terrett, Ph.D., CSO, EnsembleMacrocycles are found widely in nature and several are marketed as drugs with good pharmaceutical properties. This talk will describe how Ensemble can rapidly generate millions of synthetic macrocycles using DNA-programmed chemistry, and how they are efficiently screened against protein-protein interaction targets to identify hit compounds and SAR. The novel approach will be illustrated with successful examples of lead discovery programs, including the discovery of novel dimeric macrocyclic XIAP antagonists.
10:45 A Novel Cyclic Peptide Drp1 Inhibitor Diminishes Aberrant Mitochondrial FissionNir Qvit, Ph.D., Postdoctoral Fellow, Chemical and Systems Biology, Stanford UniversityI will address several key issues regarding constrained peptides, such as, cyclization, peptidomimetic and peptide modification. Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective cyclic peptide inhibitor of excessive mitochondrial fission. This novel cyclic peptide inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons. I will present some unpublished data from our lab to support my conclusions.
11:15 Conformational Sampling of Macrocycles Sponsored by at Speed: An Unmet NeedPaul Hawkins, Ph.D., Applications Science Group Leader, OpenEye Scientific SoftwareThis presentation will focus on relevant conformational sampling of macrocycles at high speed. In our solution we combine an unbiased sampling method with efficient global optimization to sample thoroughly the relevant conformational space of macrocycles on a time scale of minutes rather than hours.
11:30 A Macrocyclic Peptide Inhibitor of Complement C5 as an Alternative to Monoclonal Antibody TherapyDouglas A. Treco, Ph.D., President and CEO, Ra Pharmaceuticals, Inc.
12:00 pm Macrocycle Conformational Analysis, Sponsored by A Tool For Rational Macrocycle DesignDan Sindhikara, Senior Scientist, Structure-based ADME/Macrocycles, SchrödingerWe present an approach for efficient and accurate exploration of the conformational space of both peptidic and non-peptidic macrocycles. A comprehensive understanding of the conformational properties of a given macrocyclic ligand allows for the accurate prediction of membrane permeability and bioavailability. It also opens the door for rational macrocycle design in terms of both cyclization strategies as well as rigidification of existing macrocycles to further enhance their binding potency. We present our current progress towards these goals in terms of algorithm performance, development of analysis techniques, and synthesis with complementary tools.
12:30 Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing) and Poster Awards
NEW TARGETS FOR MACROCYCLICS
1:40 Chairperson’s RemarksEric Marsault, Ph.D., Professor, Pharmacology, University of Sherbrooke
1:45 p53/HDM2 Case Study: Macrocyclic Organo-Peptide Hybrids as Molecular Scaffolds for Targeting PPIsRudi Fasan, Ph.D., Associate Professor, Department of Chemistry, University of RochesterThis talk will present novel methodologies developed in our group for constructing macrocycles with a hybrid peptidic/non-peptidic backbone through the embedding of non-proteogenic, synthetic elements into genetically encoded peptidic frameworks. In recent studies, we established that these macrocyclic scaffolds can readily accommodate a-helical protein binding motifs. A case study will be discussed in which this strategy was applied to obtain macrocyclic inhibitors of the p53:HDM2 interaction that display dual specificity against the HDMX homolog as well as favorable proteolytic stability and cell penetration properties.
2:15 A Macrocyclic Peptide Inhibitor of Complement C5 as an Alternative to Monoclonal Antibody TherapyDouglas A. Treco, Ph.D., President and CEO, Ra Pharmaceuticals, Inc.
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Macrocyclics and Constrained PeptidesBigger, Better, But Hopefully Still Oral, Small Molecules
THIRD ANNUAL APRIL 22-23, 2015
MACROCYCLIC KINASE INHIBITORS
3:00 Nanocyclix Approach towards Unexplored Kinases: Identification of RIP2 and SIK2 Inhibitors for Application in Auto-Immune and CNS DisordersJan Hoflack, Ph.D., CSO, Oncodesign BiotechnologyOncodesign’s chemical biology approach using its macrocyclic chemistry platform has allowed the identification of potent and selective inhibitors for RIP2 and SIK2 kinases. The molecules have been used as chemical probes to validate the potential of these novel targets. Data will be presented that demonstrate the potential role of RIP2 as a target of interest in auto-immune diseases and for SIK2 in neuroprotection/ageing. The discovery and optimization of the inhibitors will be presented.
3:30 PF-06463922, a Novel Small Molecule Inhibitor of ALK/ROS1 with Preclinical Brain Availability and Broad Spectrum Potency against ALK-Resistant MutationsTed W. Johnson, Ph.D., Research Fellow, Medicinal Chemistry, Pfizer OncologyPF-06463922, a novel macrocyclic inhibitor of ALK/ROS1, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutants representing all of the patient crizotinib resistant mutations reported to date. Successful optimization of molecular weight and lipophilic efficiency leveraging structure-based drug design techniques led to ligands with overlapping broad spectrum potency, low transporter efflux, and brain penetration. PF-06463922 is currently in Phase 1/2 clinical trials.
4:00 Discovery of SB1578 - A JAK2 Small Molecule Macrocycle for Autoimmune DiseasesAnthony D. William, Ph.D., Senior Scientist, The Agency for Science, Technology and Research (A*STAR)-ICES
SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also demonstrates potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. Herein the design and optimization of the macrocyclic Jak2/Flt3 inhibitor will be discussed including the biochemical and cellular activities of SB1578 that translate into its high efficacy in rodent models of arthritis.
4:30 LATE BREAKING FEATURED PRESENTATION: Invention of Macrocyclic HCV NS3 Protease Inhibitors: Vaniprevir and GrazoprevirJohn A. McCauley, Ph.D., Director, Medicinal Chemistry, Merck & Co., Inc.Hepatitis C virus (HCV) infection is a global health problem of significant magnitude compared to other chronic infections. An all-oral, more convenient treatment regimen that is effective for a greater proportion of infected individuals has long been desired by patients and healthcare providers. Efforts toward improved HCV treatment include the development of antiviral agents, which inhibit key steps in viral replication. Merck has successfully targeted the HCV NS3/4a protease and HCV NS5a replication complex and is making progress towards a combination, all-oral, pan genotypic treatment regimen of short duration. This presentation describes the discovery of inhibitors of HCV NS3/4a protease, vaniprevir (MK-7009) and grazoprevir (MK-5172) with an emphasis on collaborative efforts with molecular modeling to design novel and proprietary compounds, one of which has a macrocyclic structure, and are undergoing phase III combination trials.
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Fragment-Based Drug DiscoveryFrom Hits to Leads and Lessons Learned
TENTH ANNUAL APRIL 22-23, 2015
WEDNESDAY, APRIL 22
12:30 pm Registration
NEW CHEMISTRY/NEW TARGETS
1:30 Chairperson’s RemarksDaniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.
»1:40 FEATURED PRESENTATION: Using Fragment-Based Lead Discovery towards Alternate Mechanisms: Inhibiting Ubiquitin Binding to USP7
Till Maurer, Ph.D., Senior Scientist, Structural Biology, GenentechSmall molecule inhibitors targeting the deubiquitinase Ubiquitin Specific Protease 7 (USP7) have potential as cancer therapeutics. Using ligand-based NMR in an activity agnostic FBLD effort, we have identified binders to several sites in USP7 including a unique
site in the “palm” of USP7. These could be shown to be active. The palm series imply a very distinct mechanism of action independent of the catalytic triad by binding in a region involved in USP7-Ubiquitin interaction.
2:10 Irreversible Tethering: Fragment-Based Drug Discovery Technology for Covalent Enzyme and PPI Inhibitor DiscoveryAlexander Statsyuk, Ph.D., Assistant Professor, Chemistry Department, Northwestern UniversityWe developed a new technology in which weakly bound electrophilic drug-like fragments are irreversibly trapped on the catalytic or non-catalytic cysteines of protein targets. Subsequent intact protein MS can be used to identify fragment hits, allowing one to screen 100 or more fragments/day without the use of special robotic equipment. The developed technology can be used to discover covalent drug leads for enzyme inhibitors and protein-protein interaction inhibitors.
2:40 Fragment Hopping to Design Selective Inhibitors for Beta-Catenin/T Cell Factor InteractionsHaitao (Mark) Ji, Ph.D., Assistant Professor, Chemistry, University of UtahThe aberrant formation of the β-catenin/T cell factor (Tcf) complex in the canonical Wnt signaling pathway has been recognized as the major driving force for many cancers and fibroses. Crystallographic and biochemical analyses reveal that the binding modes of Tcf, cadherin and adenomatous polyposis coli (APC) with β-catenin are identical. By using a fragment hopping technique, we have successfully designed and synthesized potent small-molecule β-catenin/Tcf inhibitors with high selectivities over β-catenin/cadherin and β-catenin/APC interactions.
3:10 The Application of Extended Huckel Theory Sponsored by for Pharmacophore ModelingAlain Ajamian, Ph.D., Director, Chemical Computing GroupRocky Goldsmith, Ph.D., Applications Scientist, Chemical Computing GroupPharmacophore models play an essential role in drug discovery. Generating
pharmacophore models which encode accurate molecular recognition features are highly dependent on properly defined annotation points. Here we have developed a new approach for pharmacophore modeling which is based on a semi-empirical method using Extended Hückel Theory (EHT). The pharmacophore features generated through the EHT annotation scheme take into account ligand resonance and electron withdrawing effects and are sensitive to non-standard interactions, such as C-H and halogen bond interactions, during pharmacophore screening.
3:40 Celebratory 10th Annual Refreshment Break in the Exhibit Hall with Poster Viewing
4:20 Kinetic Target-Guided Synthesis: A Fragment-Based Lead Discovery Strategy based on the Bioorthogonal Sulfo-Click ReactionRoman Manetsch, Ph.D., Associate Professor, Department of Chemistry and Chemical Biology, Northeastern UniversityKinetic Target-Guided Synthesis (TGS) has been developed, in which the biological target is actively engaged in the irreversible assembly of its own inhibitory ligand from a library of reactive fragments. The Manetsch laboratory developed the first kinetic TGS approach for the identification of compounds disrupting protein-protein interactions. We demonstrated that the sulfo-click reaction, an amidation reaction between thio acids and sulfonyl azides, is suitable for a kinetic TGS approach targeting proteins of the Bcl-2 family.
4:50 Identification of Fragment Hits that Bind the SAM pocket of COMTMark S. Hixon, Ph.D., Senior Fellow Modeling & Simulation, Global DMPK, Takeda California, Inc. Catechol O-methyl transferase (COMT) is a S-adenosyl-l-methionine transferase. Catechol analog inhibitors of COMT prolong dopa lifetimes extending relief in Parkinson’s disease. To avoid some of the liabilities associated with catechol analogs we conducted a fragment-based screening approach to discover COMT inhibitors targeting the SAM binding pocket. We identified a series of ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). In addition we solved the first SAM-competitive small-molecule COMT co-complex crystal structure.
5:20 Breakout DiscussionsIn this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.
6:20 Close of Day
6:30 Dinner Short Courses**Separate registration required; please see page 4 for details
Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA 02494www.healthtech.com
Final Weeks to Register!Record Attendance this Year
Fragment-Based Drug DiscoveryFrom Hits to Leads and Lessons Learned
TENTH ANNUAL APRIL 22-23, 2015
THURSDAY, APRIL 23
8:00 am Morning Coffee
»8:30 PLENARY KEYNOTE PRESENTATION: Fragment-Based Drug Discovery: A Fifteen Year (Re-)Evolution
Harren Jhoti, Ph.D., President & CEO, Astex Pharmaceuticals(please see page 2 for details)
9:30 Coffee Break in the Exhibit Hall with Poster Viewing
BEST PRACTICES, ADVANCES AND CHALLENGES IN FRAGMENT-BASED DISCOVERY
10:10 Chairperson’s RemarksRoderick E. Hubbard, Ph.D., Director, Chemistry, Vernalis Research and University of York
10:15 Fragment Libraries and Screening the “Undruggable”Justin Bower, Ph.D., Head, Chemistry and Structural Biology, Drug Discovery, The Beatson Institute for Cancer ResearchThis presentation will outline our approach to fragment library design and how we have incorporated descriptors of shape and complexity to complement more traditional approaches. I will also describe our approach to targeting several GTPases implicated in cancer.
10:45 Design of the Merck Fragment Library 2014: Incorporating Biologically Privileged Motifs, the Ability to Efficiently Interrogate SAR, and Expert Chemists’ AssessmentPeter Kutchukian, Ph.D., Associate Principal Scientist, ChemInformatics, Merck and Co.As opposed to focusing on desirable properties for a library (shape, physical properties, etc), the more novel design principles applied to the library will be described. Namely, 1) an integrated chemogenomics database of internal and external data was used to identify biologically privileged motifs for incorporation in the library, 2) library members and expansion analogues were selected based on a “diversified portfolio” approach to fragment hit follow up as opposed to the more standard nearest neighbor follow-up, and 3) visualization tools were built to empower medicinal chemists to readily use these guiding principles to select (or design) fragments that fulfilled these goals.
11:15 Advances in SPR Fragment Screening Sponsored by
Andrew L. Hopkins, DPhil, SULSA Research Professor, Translational Biology, University of DundeeSPR has become the workhorse method for rapid and accurate fragment screening. We present results from a collaborative effort between the Hopkins-Navratilova lab and GE Healthcare prototyping new assays methods and new technology to advance SPR fragment screening. We will introduce the first results on a new, prototype Biacore™ instrument.
11:30 Experiences with Fragment Libraries at AstexAlison Woolford, Ph.D., Associate Director, Chemistry, Astex PharmaceuticalsThe Astex library has been through multiple rounds of enhancement since the last publication. Armed with thousands of proprietary protein-fragment crystal structures, across a wide range of protein families generated over 10 years, we will discuss how later iterations of the fragment library have been constructed and analysed. We will show how the fragment hit rate varies with lipophilicity and heavy atom count, and compare the hit rates of 2D versus 3D fragments. We will also present a recently disclosed initiative involving minimal binding pharmacophore elements that are appropriate for fragments and show how they have been used to drive library enhancement. These privileged pharmacophores have added value by generating novel fragment hits for progression into hit to lead chemistry.
12:00 pm Ligand Deconstruction and Library Design: Why Some Fragment Positions Are Conserved and Others Are Not?Sandor Vajda, Ph.D., Professor, Biomedical Engineering and Chemistry, Boston UniversityFBDD relies on the premise that the binding mode of fragments is conserved upon expansion to a ligand. This hypothesis is frequently tested by deconstructing ligands into their fragments, and by determining whether the fragments still bind, and if they do, whether their locations are conserved. We show that a condition for fragment conservation can be developed in terms of binding hot spots, i.e., regions of the protein where interactions with any ligand contribute a large fraction of the binding free energy. The condition can be used to predict fragment size and shape in a library to be screened for a specific target, including non-traditional PPI targets and proteins that can be targeted only by macrocycles.
12:30 Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing) and Poster Awards
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Fragment-Based Drug DiscoveryFrom Hits to Leads and Lessons Learned
TENTH ANNUAL APRIL 22-23, 2015
1:45 Attacking Cancer with Fragments: BCL-2, MCL-1, and ApoptosisAndrew Petros, Ph.D., Associate Research Fellow, Research & Development, AbbVieABT-263 (navitoclax) is a potent inhibitor of the anti-apoptotic proteins BCL-XL and Bcl-2 and has proven effective against several types of B-cell derived cancers. However, thrombocytopenia driven by BCL-XL inhibition has been dose-limiting for navitoclax in the single agent setting. In attempt to overcome this side effect we have employed fragment-based methods to obtain a BCL-2 selective compound which could serve as a starting point for the development of a BCL-2 selective anti-cancer agent. Such an agent would potentially overcome the BCL-XL mediated thrombocytopenia observed with ABT-263. In addition, fragment screening methods and structural biology have been used to drive discovery of novel inhibitors for the pro-survival protein MCL-1. MCL-1 has been shown to be a resistance factor for ABT-263. Cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts.
2:15 Choosing and Using Fragments in Oncology Lead DiscoveryRoderick E. Hubbard, Ph.D., Director, Chemistry, Vernalis Research and University of YorkFragment methods have been used successfully for many oncology targets – to assess ligandability, to provide chemical tools to probe and validate target biology, and to generate candidates to progress into clinical trials. I will review some of our recent experiences in using fragments for lead and candidate discovery, with particular emphasis on the very early stages of developing fragment and early hit SAR to decide on which series to progress.
2:45 Refreshment Break
3:00 Exploring Possible Drug Target Conformational Changes by Fragment ScreeningBarry Finzel, Ph.D., Professor, Medicinal Chemistry, University of MinnesotaInhibitors of Mycobacterium tuberculosis BioA with high ligand efficiency have been identified by screening for compound-induced Tm shifts with Differential Scanning Fluorimetry (DSF). Structures with bound fragments sample an ensemble of different active site conformations that correlate with ligand binding. DSF shows that some of the ligands destabilize protein folding, while others are stabilizing, even though dissociation constants obtained by ITC are similar. Destabilizing ligands should not be ignored when searching for lead compounds.
3:30 Use of FBDD in the Discovery of Two Series of Potent Methionine Aminopeptidase-2 InhibitorsChris McBride, Staff Scientist, Medicinal Chemistry, TakedaThis presentation will demonstrate the strategy used to identify two series of methionine aminopeptidase-2 (MetAP2) inhibitors. Fragment libraries were screened for hits with high ligand-efficiency (LE) and orthogonal hit confirmation led to a low affinity indazole core being selected for directed elaboration with the aid of structural information. Additionally, structural insight and SAR from the indazole series led to the design and accelerated knowledge-based fragment growth of the pyrazolo[4,3-b]indoles as MetAP2 inhibitors.
4:00 FBDD on Metalloprotein TargetsSeth M. Cohen, Ph.D., Professor, Department of Chemistry and Biochemistry, University of California, San DiegoMost inhibitors of alloproteins employ a functional group that binds to the active site metal ion. We have developed an FBDD approach to metalloenzyme inhibitors by developing a library of suitable metal-binding pharmacophores (MBPs). Thermodynamic and structural investigations are being used to provide insight into the influence of the protein active site on MBP binding. In this presentation, our efforts on utilizing these MBPs for metalloprotein inhibition will be discussed.
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Hotel & Travel Information
Conference Hotel:
Hilton San Diego Resort & Spa1775 East Mission Bay DriveSan Diego, CA 92109Phone: 619-276-4010Discounted Room Rate: $199 s/dDiscounted Cut-off Date: March 24, 2015
Please visit our conference website to make your reservation online or you may call the hotel directly to make your sleeping accommodations. You will need to identify yourself as a CHI conference attendee to receive the discounted room rate with the host hotel. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space- and rate-availability basis. Rooms are limited, so please book early to take advantage of the discount we have negotiated.
The Hilton San Diego Resort & Spa is a TripAdvisor Certificate of Excellence recipient. It is located directly on Mission Bay and is a short, 10 minute taxi ride from the San Diego International Airport. In addition to its stunning location, our conference attendees will enjoy:
• Newly renovated guest rooms
• Unlimited use of the resort’s modern, state-of-the-art Fitness Center
• World class swimming pool
• Breathtaking views and award winning restaurants
• Beachside firepits for evening relaxation
• Complimentary shuttle to Historic Old Town and Gaslamp Quarter
We understand that you have many choices when making your travel arrangements. Please understand that reserving your room in the CHI room block at the conference hotel allows you to take full advantage of the conference sessions, events and networking opportunities, and ensures that our staff will be available to help, should you have any questions about your accommodations.
Car Rental Discounts:
Special discount rentals have been established with Hertz for this conference.
• Go to www.hertz.com and enter Convention Number (CV): 04KL0006
Or Call Hertz directly at 800-654-3131 and reference our Discount Number 04KL0006
Visiting San DiegoWith its great weather, miles of sandy beaches, and major attractions, San Diego is known worldwide as one of the best tourist destinations. International and commercial air service for the region is provided by the San Diego International Airport. The Online Transit Information System (“Otis”) lets you find out how to get around San Diego using the Metropolitan Transit System’s buses, trolleys, or trains.
Some San Diego Highlights• The Gaslamp Quarter is Southern California’s premier dining, shopping and entertainment district, where you’ll find a truly eclectic blend of food, fun and culture all within one of San Diego’s most historic areas.
• Just south of Mission Valley and known as the birthplace of California, Old Town teems with a lively, authentic atmosphere, boasting museums, historical sites and restaurants.
• At the world-famous San Diego Zoo, you’ll see some of the world’s rarest wildlife including giant pandas and koalas. A visit to the San Diego Wild Animal Park is like a safari to many of the world’s most exotic places.
• World-renowned Balboa Park is home to fifteen museums, various arts and international culture associations, as well as the San Diego Zoo, making it one of the nation’s largest cultural and entertainment complexes.
• SeaWorld San Diego entertains, amazes and educates, creating memories that will last a lifetime. See live shows, ride the rides, and get up-close to beluga whales, polar bears, sharks and penguins.
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Sponsorship, Exhibit, and Lead Generation Opportunities
CHI offers comprehensive sponsorship packages which include presentation opportunities, exhibit space, branding and networking with specific prospects. Sponsorship allows you to achieve your objectives before, during, and long after the event. Any sponsorship can be customized to meet your company’s needs and budget. Signing on early will allow you to maximize exposure to qualified decision-makers.Podium Presentations – Available Within the Main Agenda!
Showcase your solutions to a guaranteed, targeted audience. Package includes a 15- or 30-minute podium presentation within the scientific agenda, exhibit space, on-site branding, access to cooperative marketing efforts by CHI, and more.
Breakfast & Luncheon Podium Presentations
Opportunity includes a 30-minute podium presentation. Boxed lunches are delivered into the main session room, which guarantees audience attendance and participation. A limited number of presentations are available for sponsorship and they will sell out quickly. Sign on early to secure your talk!
Invitation-Only VIP Dinner/Hospitality Suite
Sponsors will select their top prospects from the conference pre-registration list for an evening of networking at the hotel or at a choice local venue. CHI will extend invitations and deliver prospects, helping you to make the most out of this invaluable opportunity. Evening will be customized according to sponsor’s objectives i.e.:
• Purely social• Focus group• Reception style• Plated dinner with specific conversation focus
Exhibit
Exhibitors will enjoy facilitated networking opportunities with qualified delegates. Speak face-to-face with prospective clients and showcase your latest product, service, or solution.
Additional branding and sponsorship opportunities available!
Looking for additional ways to drive leads to your sales team? CHI’s Lead Generation Programs will help you obtain more targeted, quality leads throughout the year. We will mine our database of 800,000+ life science professionals to your specific needs. We guarantee a minimum of 100 leads per program! Opportunities include:
• Whitepapers • Web Symposia• Custom Market Research Surveys• Podcasts
For additional information please contact:
Carolyn Benton Business Development Manager 781-972-5412 | [email protected]
2015 Exhibitors & Sponsors (As of December 3, 2014)
ADDITIONAL REGISTRATION DETAILSEach registration includes all conference sessions, posters and exhibits, food functions, and access to the conference proceedings link.Handicapped Equal Access: In accordance with the ADA, Cambridge Healthtech Institute is pleased to arrange special accommodations for attendees with special needs. All requests for such assistance must be submitted in writing to CHI at least 30 days prior to the start of the meeting.To view our Substitutions/Cancellations Policy, go to www.healthtech.com/regdetailsVideo and or audio recording of any kind is prohibited onsite at all CHI events.
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A series of diverse reports designed to keep life science professionals informed of the salient trends in pharmaceutical technology, business, clinical development, and therapeutic disease markets.For a detailed list of reports, visit InsightPharmaReports.com, or contact Adriana Randall, [email protected], +1-781-972-5402.
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CONFERENCE PRICING
Commercial Academic, Government, Hospital-affiliated 1 Short Course $699 $399
2 Short Courses $999 $699
3 Short Courses $1199 $799
4 Short Courses $1299 $899
STANDARD PACKAGE (Includes Access to Two Conferences, Excludes Short Courses)
Registrations after March 20, 2015 and on-site $2599 $1299
BASIC PACKAGE (Includes Access to One Conference, Excludes Short Courses)
Registrations after March 20, 2015 and on-site $1899 $1049
SHORT COURSES
CONFERENCE SELECTIONS:
April 21-22 (Tuesday-Wednesday) April 22-23 (Wednesday-Thursday)
Track 4: Kinase Inhibitor ChemistryTrack 5: Macrocyclics and Constrained PeptidesTrack 6: Fragment-Based Drug Discovery
Morning Short Courses (April 20)SC1: Trends in Physical Properties of Drugs
Afternoon Short Courses (April 20)SC2: GPCR Structure-Based Drug DiscoverySC3: Molecular Interactions and Drug DesignSC4: Introduction to Targeting Bromodomains
Dinner Short Courses (April 20)SC5: Analyzing and Rationalizing Protein-Peptide InteractionsSC6: Immunology Basics for Chemists
Dinner Short Courses (April 22)SC7: Macrocycles in Drug Discovery: Opportunities, Challenges and StrategiesSC8: Advancing Tools and Technologies for Fragment-Based DesignSC9: Introduction to Targeted Covalent InhibitorsSC10: Introduction to Targeting the Ubiquitin Proteasome System (UPS)
CONFERENCE DISCOUNTS
POSTER DISCOUNT ($50 Off) Poster abstracts are due by March 20, 2015 Once your registration has been fully processed, we will send an email containing a unique link allowing you to submit your poster abstract. If you do not receive your link within 5 business days, please contact [email protected]. * CHI reserves the right to publish your poster title and abstract in various marketing materials and products.REGISTER 3 - 4th IS FREE: Individuals must register for the same conference or conference combination and submit completed registration form together for discount to apply. ALUMNI DISCOUNT: Cambridge Healthtech Institute (CHI) appreciates your past participation at Drug Discovery Chemistry. As a result of the great loyalty you have shown us, we are pleased to extend to you the exclusive opportunity to save an additional 20% off the registration rate. Please note: Our records must indicate you were an attendee of Drug Discovery Chemistry in the past in order to qualify.
GROUP DISCOUNTS: Discounts are available for multiple attendees from the same organization. For more information on group rates contact Uma Patel at +1-781-972-5447Alumni, Group, and ‘Register 3 & 4th is Free’ discounts cannot be combined.
How to Register: [email protected] • P: 781.972.5400 or Toll-free in the U.S. 888.999.6288
Please use keycode DCH F when registering
Cover
Short Courses
Sponsor & Exhibit Opportunities
Fragment-Based Drug Discovery
Macrocylics and Constrained Peptides
Kinase Inhibitor Chemistry
Conference-at-a-Glance
Plenary Keynotes
Distinguished Faculty
Hotel & Travel Information
Epigenetic Inhibitor Discovery
Welcome
Inflammation Inhibitors
Protein-Protein Interactions
Registration Information
Click Here to Register Online!
DrugDiscoveryChemistry.com
Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA 02494www.healthtech.com
Final Weeks to Register!Record Attendance this Year
