DRUG DISCOVERY SERVICES State-of-the-art technology platforms combined with highly experienced scientists with expertise in a broad range of therapeutic areas CAPABILITIES INCLUDE New capabilities in anti-infectives Target identification & validation Screening Hit-to-lead & lead optimisation Medicinal chemistry In vivo & in vitro pharmacology Proteomics Biomarker science Compound management Integrated drug discovery
DD up SPECIAL EDITION CAPABILITIES INCLUDE New capabilities in anti-infectives Target identification & validation Screening Hit-to-lead & lead optimisation Medicinal chemistry In vivo & in vitro pharmacology Proteomics Biomarker science Compound management Integrated drug discovery STATE-OF-THE-ART TECHNOLOGY PLATFORMS COMBINED WITH HIGHLY EXPERIENCED SCIENTISTS WITH EXPERTISE IN A BROAD RANGE OF THERAPEUTIC AREAS DRUG DISCOVERY SERVICES
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DDupSPECIALEDITION
CAPABILITIES INCLUDENew capabilities in anti-infectivesTarget identification & validationScreeningHit-to-lead & lead optimisationMedicinal chemistryIn vivo & in vitro pharmacologyProteomicsBiomarker scienceCompound managementIntegrated drug discovery
STATE-OF-THE-ART TECHNOLOGY PLATFORMS COMBINED WITH HIGHLY EXPERIENCED SCIENTISTS WITH EXPERTISE IN A BROAD RANGE OF THERAPEUTIC AREAS
ing with Evotec, our partners gain access to an industry-leading team of scientists with years of experience in the Pharma and biotech industry. This experience effectively marries target and disease biology exper-tise with a world-class technology infrastructure. These scientists have successfully delivered clinical candi-dates in their past careers but more importantly they continue to do so at Evotec for our clients. The intel-lectual input of Evotec’s scientists is one of the pillar’s supporting Evotec’s business model. The most visible sign of our scientist’s ability to deliver innovative solutions is the number of customer patents on which Evotec scientists are named inventors. This number grows yearly and currently exceeds 200 and covers many thera-peutic areas and target classes.
Evotec is the partner of choice for stand-alone services which are charged on a purely fee-for-service basis. Alter-natively, we can offer holistic, fully integrated drug discovery solutions through a va riety of commercial struc-tures. Our aim is to meet your require-ments for the drug discovery solution you are seeking both scientifically and commercially. Our track record is second to none as testified by the number of projects that have moved through to the clinic and the strong portfolio of satisfied partners we have worked with through the years.
Drug development is a high-reward but high-risk process, with as few as one in 10,000 new molecular enti-ties making the successful but costly and lengthy journey from discovery to market. The pharmaceutical indus-try is struggling with the fall in R&D productivity and increasing demands from the regulatory authorities who demand first- and best-in-class thera-pies rather than me-toos.
Evotec’s drug discovery platform was established to deliver an industrial-ised, cutting-edge, comprehensive and unbiased infrastructure to meet the industry’s need for innovation in drug discovery. Using a strategic outsourcing partner like Evotec to drive Innovation Efficiency, reduces the risk and increases the chance of success in drug discovery without the need for the industry to invest in fixed cost structures.
Evotec’s portfolio of capabilities includes target identification and validation, compound management, screening, hit-to-lead and lead opti-misation medicinal chemistry, in vivo and in vitro pharmacology, prote-omics and biomarker science. Work-
Evotec has been involved in more than 250 partnerships since its incep-tion in 1993 and has delivered more than 30 pre-clinical candidates and 20 clinical candidates both in partner-ships and within its own proprietary drug discovery efforts.
This document showcases the state-of-the-art offerings of Evotec to address the challenges of Innovation Efficiency within our industry. In particular with this Drug Discovery Services update we introduce you to our new capabilities in anti-infective research. Earlier this year we acquired Euprotec, a UK based company with one of the world leading platforms for infectious disease research. This acquisition gives us access to Strain-Bank, a unique collection of clini-cal isolates useful in establishing the activity profiles of compounds against bacterial and fungal pathogens as well as key capabilities in microbiology, pharmacology and DMPK. Of critical importance is the key team of scien-tists from Euprotec that have now become a part of the Evotec family.
Please use this document to define how we can help you and contact us for the most innovation- and cost-efficient solution to your drug discovery requirements.
Yours sincerely Mario Polywka
INNOVATION EFFICIENCYWITH EVOTEC
A message from Evotec Chief Operating Officer, Dr Mario Polywka
Evotec’s specialist group in the infectious disease therapeutic area boasts state-of-the-art microbiology facilities including a unique and highly characterised strain bank. The group was established in 2008 as Euprotec and was acquired by Evotec in May 2014. The group provides bespoke anti-infective drug discovery and development services to a growing number of global clients and brings to Evotec an established track record in collaborating to discover and develop therapies and vaccines to treat and prevent serious and life-threatening infections resulting from multi-drug resistant bacteria and fungi including MRSA, Pseudomonas, and Clostridium difficile.
In 2012, Euprotec was named the Bionow “Biomedical Service Provider“ of the Year in recognition of delivering scientific excellence and the very best in customer service to all of its clients. The group’s offering is fully integrated with the wider discovery platform at Evotec to enable us to offer either standalone microbiology services or conduct fully integrated anti-infective drug discovery projects. Key capabilities of Evotec’s microbiology group fall into the four areas of EvostrAInTM, Microbiology, Pharmacology and ADME/PK/PD as follows:
EvostrAInTM
EvostrAInTM is a unique collection of clinical isolates that can be used to establish the activity profile of lead compounds and candidates. A key feature is that the isolates are highly characterised and, in many cases, mechanisms of resistance defined. Our strain collection contains an extensive range of geographically diverse human bacterial and fungal pathogens that cover isolates susceptible and resistant to current antimicrobial drugs.
MICROBIOLOGYWe employ industry-standard methods including CLSI, EUCAST and BSAC to test compounds for antimicrobial activ-ity against organisms from our
extensive collection, EvostrAInTM, or strains provided by our collabo-rators. This includes the ability to conduct whole-cell screening for antimicrobial activity for hit iden-tification, MIC, MBC/MFC, time-kill and PAE studies using single or combination agents, hollow fibre PK/PD or bioreactor human cell systems for detailed profiling for characterisation of novel anti-infective agents and compound/drug combination studies for assessment of synergistic, antago-nistic and additive effects. Bespoke methods for susceptibility profiling can be developed for testing novel agents where standardized methods may not be appropriate. In parallel mechanism of action and resistance frequency assays can be performed.
PHARMACOLOGYWe specialise in assessing the efficacy of lead and candidate compounds in highly relevant and validated disease models. Our extensive range of established models are well-suited to the develop ment of multiple classes of agent including small molecules, natural products, peptides, antibodies, other biologics and vaccines. We provide a highly bespoke service, customising stud-ies to meet the exact requirements based on programme needs and parameters/endpoints of interest.
NEW CAPABILITIESIN ANTI-INFECTIVE RESEARCH
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Lloyd Payne Senior Vice President Anti-infectives Operations
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For agent efficacy assessment against bacterial and fungal infection our models can address different sites of infection (localised and systemic) by Gram-positive (including Staphylococcus aureus, Streptococcus pneumoniae, and others), Gram-negative (including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumanii and others), anaerobes (including Clostridium difficile) or fungal species (including Candida sp., Aspergillus sp., Mucorales, Malassezia sp.).
ADME/PKOur existing extensive ADME/PK offering is now enhanced with the ability to address anti-infective specific capabilities. In addition to high quality pharmacokinetic profiling and bioanalysis these include: a) Bioassay/bioactivity drug quantificationb) Development of bespoke PK models and assays with drug quantification at multiple sitesc) Translation of PK data into
efficacy models to optimise outcomesd) Tolerability assessment utilising multiple endpointse) Early assessment of cytotoxicity potential against multiple mammalian cell lines.
In particular, Euprotec specialises in PK/PD profiling and modelling in multiple disease models.
TARGET IDENTIFICATIONAND VALIDATION
models coupled with a variety of read-outs including high-content screening are designed to provide an accelerated solution to target identification and validation. Our offering includes: Screening of siRNA libraries for target identification
Validation of specific targets in various cellular models using disease-relevant read-outs
Evotec has built substantial ex- perience in this area and routinely achieves knock-down effi ciencies of at least 80%. Additionally, expertise in working with non-traditional cellular models such as co-cultures and cellular aggregates is available.
IN VIVO TARGET VALIDATION
Evotec has disease models in a number of areas such as dia betes, diabetic complications, kidney diseases, neurodegeneration, oncology, inflammation and pain that can be used for target valida-tion. Approaches utilised include: Application of target-selective small molecules or biologics in acute or sub-chronic in vivo studies in rodents
Virus-based target in vivo knock-down and over-expression techniques
Andreas Scheel Executive Vice President In vitro BiologyIn vitro Pharmacology
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OFFERINGEvotec has established a world-leading platform to support the discovery and validation of inno-vative disease-modifying targets across different therapeutic areas. Our offering comprises: Differential expression studies followed by bioinformatics-driven data mining and hypothesis building
Knock-down and over-expression studies both in vitro and in vivo as well as access to relevant in vivo disease models
World-class ex vivo imaging tech-nology platform using tissue sections to study cellular and molecular events
Phenotypic screening of complex cellular systems for hit iden- tifi cation
Target deconvolution using proteomics
GENE EXPRESSION PROFILINGChanges in gene expression, as result of a disease state or as a consequence of drug action, give invaluable insights into biological systems. From early target iden-tification to mode of action stud-ies and biomarker identification the analysis of gene expression data supports the drug discovery processes. Our capabilities include: Design and execution of tran-scriptomics studies in vitro or in vivo including rigorous quality control
Bioinformatics analysis to deter-mine differential expression and generate annotated gene lists
Cluster analysis to identify groups of regulated genes
Data interpretation turning raw data into meaningful biological and pharmacological information
IN VITRO TARGET MODULATION CAPABILITIES
The powerful combination of siRNA and disease-related cellular
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A variety of read-outs have been established that allow the investi-gation of target modulation. Such studies are run on a routine basis and additional read-outs are devel-oped on a continuous basis. Classical pharmacodynamic and efficacy read-outs such as blood glucose and HbA1c for diabetes, behavioural read-outs for pain and neurodegeneration
A world-class ex vivo histology and immunohistochemistry plat-form investigating cellular and molecular markers in tissue sections prepared from treated animals
USE OF PHENOTYPIC ASSAYS TO IDENTIFY NEW
DISEASE RELEVANT TARGETS AND PATHWAYS
The ability to study compound effects in a disease-relevant cell type in a target-unbiased way offers enormous potential and has thus become increasingly popular in recent years, with more complex and disease-relevant cellular systems becoming available for higher throughput assays.
Evotec has in-depth expertise in the area of phenotypic screening and target deconvolution.
High-Content ScreeningEvotec has a world-class high-content screening platform that is increasingly used for hit identifica-tion through phenotypic screening >15 years know-how in the design and implementation of pheno-typic assays using cell lines but also including complex cellular systems utilising primary cells and stem cells in the area of neurode-generation, inflammation, meta-bolic disease and oncology
A small molecule compound library of 400,000 compounds
Identification of new mechanisms to treat kidney disease: Phenotypic screening of conditionally immortalised human podocytes
Proteomics-based target deconvolution
Evotec has established a mass spectrometry-based approach to ex perimentally determine the bin-ding partner(s) of a lead compound in a relevant cellular context: Metabolic or chemical labelling Optimised linker chemistry capa-bilities
Determination of Kd values for each putative binding partner
Combine with post-translational events to understand global cellu-lar effects
Overview of Evotec capabilities and expertise in target identification and validation across different disease areas
OFFERINGEvotec has a long history in high-throughput screening (“HTS”) utilis-ing large client compound collections and also our own 400,000 compound collection. Evotec’s screening platform is differentiated through integrating a variety of detection technologies with high-throughput capabilities. This technology platform allows for assay miniaturisation and use of multiple read-out parameters to enable the reduction of false positives and nega-tives. Evotec’s technology platform
Dirk UllmannExecutive Vice President Lead Discovery
includes nuclear magnetic resonance spectrometry (“NMR”), surface plas-mon resonance spectrometry (“SPR”), high-content screening (“HCS”) and high-throughput mass spectrometry based screening (“HTMS”).
OVERVIEW SCREENING CAPABILITIES AT EVOTEC
Evotec selects the most suitable screening strategy for your target – our approach is to let the target dictate the screening strategy and not the other way around.
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EVOSCREEN MARK II EVOSCREEN MARK III 384-HTS SYSTEM RADIOMETRIC PLATFORM
No. of Systems 1 1 3 semi-automated benchtop devices
Plates 2080-well 1536-well 384-well 96 and 384-well
Formats Biochemical Cellular + Biochemical
Cellular + Biochemical
Cellular + Biochemical
Readers Insight™ FCS+plus reader
PE EnVision FLIPRTetra, PE EnVision, Tecan Safire, RapidFire MS
PE TopCount (2) PE MicroBeta2 (3)
Assay principles Binding Enzyme activity
Binding Enzyme activity Reporter gene
Binding Enzyme activity
Ca2+ flux Second messenger Membrane potential
Radioligand binding FlashPlate
SPA Filtration
Detection FCS+plus Fluorescence, Luminescence,
Absorption, Alpha screen
Fluorescence, Lumi-nescence, Absorption, Alpha screen, Mass
spectrometry*
Isotopes: 3H, 35S, 14C, 32P, 33P,
59Fe, 125I
Throughput up to 100,000 / day up to 100,000 / day up to 40,000 / day up to 25,000 / day
*Available RapidFire MS capacity allows for up to 10,000 data points per dayScreening platforms at Evotec
Evotec has twenty years of expe-rience in assay development; in particular in HTS, but also to support hit-to-lead & lead opti-misation (H2L/LO) programmes. Our experience includes: A broad portfolio of assays
covering the major target classes (see chart)
New target classes in the field of epigenetics and protein-protein interaction
High numbers of unique assays developed as no literature
precedence was available Assay read-outs covering a wide range of technologies including both biochemical and cellular assays
Assays using label-free and biophysical methods
Assay development and HTS track record
ASSAY DEVELOPMENT
NHR 9
Others 109Kinase 74
Ion Channel 54
ADMET 25
Phosphatase 9
Protease 67
GPCR 59
>400 assays developed Success rate >95% High percentage of cellular assays
>220 uHTS screens Specific hits with EC50<25μM identified in most screens
SCREENING
Enzyme other 79GPCR 43
Protein Protein 23
Others 20
ADMET 5Protease 16
Kinase 19
Ion Channel 19
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THE OPTIMUM SCREENING COLLECTION
Our library contains 400,000 compounds consisting of 70,000 proprietary Evotec compounds and a set of 330,000 maximally diverse “islands”.
Evotec’s screening library is differ-entiated through its quality, diver-sity and novelty and has a success-ful track record of delivering potent and attractive compounds as star-ting points for medicinal chemistry optimisation.
For structure-based approaches to drug discovery, Evotec has a 20,000 fragment set available for biochemi-cal screening and a 3,000 fragment set specifically selected for NMR and SPR screening. Evotec screens customer libraries of any size, virtual screening derived hits and also smaller, more target-directed libraries.
SCREENING PROCESSThe integration and connection of the different stages of the screen-ing process from assay develop-ment to automation to compound management/tracking and finally data processing are essential. The Evotec screening team manages this complexity on a daily basis to deliver high-quality data on time to our clients.
In Evotec’s view the success of a screening project is determined by: Target selection Right strategy for target expres-sion to address specific sites of interest
Robust and sensitive assay system Well-selected compound collec-tion for screening
Reliable screening process Careful characterisation screening hits in orthogonal test systems
Screening process
Evotec proprietary 70,000
Evotec fragment 20,000
Diverse islands 330,000
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DATA HANDLINGEvotec’s data analysis platform, Aplus, is suited to support all screening processes from HTS including multivariate analysis
Distribution of calculated properties in Evotec’s discovery screening library
for HCS to SPR and also HTMS. This software facilitates the inte-gration of all techniques into one analysis platform and streamlines the process flows. For customer
Reagent production and assay
development
Primary hits(3sigma
threshold)
Confirmed hits
Hits with conc. dependent activity
Specific hits with confirmed conc.
dependent activity
Identification of clusters &
singletons
Adaptation on screening platform
Primary HTS screen n=1
MINIATURISATIONMARKER
LIBRARY SCREENDATA STATISTICS
A+
11PT DRCS N=2+ LC/MS CHECK
TEST IN ORTHOGONAL ASSAY
PRELIMINARY SAR
HIT CONFIRMATIONSCREEN N=3
reporting, Evotec is flexible to meet customer needs in data formats for upload in different environments.
OFFERINGEvotec specialises in the development and implementation of high-content based assays for high-throughput screening and compound valida-tion to probe the pathophysiological environment. High-content-screening (“HCS”) is routinely used throughout the hit identification cascade from target validation to mechanistic stud-ies. The assays developed at Evotec encompass both a target centric as well as phenotypic approach with emphasis on tissue samples, stem
cell derived or primary cells from appropriate hosts. This approach is a core part of Evotec’s efforts to identify novel targets and drugs with disease-modifying potential.
Evotec’s HCS expertise is built around the OPERA® platform where an essential understanding of the mechanics and image analy-sis tools, gathered over a period of more than 15 years in the develop-ment of the platform, flows into the hit identification process. The platform is completed with a power-ful data management system and powerful data analysis tools includ-ing multifactorial analysis. Based on this expertise, Evotec has performed many high throughput screens of up to 350,000 compounds and devel-oped over 30 assays to study mode of action of compounds and targets in a multitude of cellular backgrounds.
Accessing Evotec’s HCS platform offers a road to novel target space achieved via an array of disease-related secondary models post-HTS coupled to target deconvolution via the application of bioinformatics, siRNA, gene expression and finally mass spectrometry based proteomic approaches.
TARGET/ASSAY EXPERTISEThe nature of HCS describes primarily a target agnostic approach
measuring phenotypic/morpho-logical changes associated with target engagement.
The use of phenotypic screening provides Evotec’s clients with a whole new realm of drug discovery opportunities that otherwise could not be addressed. This includes experienced multi-disciplinary teams that build strategies for hit follow up towards identifying the molecular mechanism of action of a potential drug. Other assay formats that are routinely devel-oped on Evotec’s HCS platform are designed to investigate subtle or rare subcellular events. The table shows examples of cellular events that Evotec has experience with on the OPERA® platform.
Ina SternbergerGroup Leader In vitro Pharmacology
PHENOTYPES Proliferation Cell cycle analysis Cell death/necrosis/apoptosis Differentiation markers DNA damage Cytoskeleton rearrangements Neurite outgrowth Mitochondrial mass Endocytosis Synapse density Neurodegeneration/-protection Intracellular aggregation Post-translation modification
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DISEASE AREA EXPERTISEHCS at Evotec is now a common element in many drug disco very programmes across a variety of ther-apeutic areas. At present, the main focus of HCS is in the area of oncol-ogy, kidney disease, diabetes, pain,
TARGET/PHENOTYPE READOUT DRUG ID PHASE
Transporter Internalisation HTS 250K
Fibrosis αSma expression/actin alignment HTS 50K
Beta cell proliferation Insulin expression coupled to BrdU stain
Diabetic Neuropathy Actin rearrangement Known drug collection
Striatal neuron development DARP32 positive cells Protocol development
Neurodegeneration/ALS Neurite outgrowth in co-culture system
10K HTS + known drugs
Transporter Binding of fluorescent ligand HTS of 100K
Huntington’s protein aggregation Number of aggregates Known drug collection
NFκB translocation Nuclear accumulation in HUVECs Lead optimisation
PTM enzyme in AID NET formation in primary human neutrophils
Compound validation
DNA repair/oncology DNA damage response in tumor cell line
HTS 50K
Autophagy LC3 accumulation in autophagosomes Pilot screen
Epigenetics Protein methylation Hit follow-up
Examples of track record
inflammation and neurodegenera-tion. Here the strengths of HCS are combined with regenerative medi-cine concepts to probe and discover new treatment paradigms such as beta cell regeneration for diabetes and podocyte protection for diabetic
neuropathy. Applying stem cell technology in phenotypic and high-content screening is also an area of active research at Evotec where we are committed to delivering new treatment paradigms for ALS and other degenerative diseases.
HIT IDENTIFICATIONSTRUCTURE-BASED DRUG DESIGN (SBDD)
OFFERINGThe SBDD platform at Evotec includes a comprehensive fragment-based drug discovery (“FBDD”) plat-form. Sensitive screening techniques, such as the FCS+plus (proprietary to Evotec) or NMR, SPR or mass spec-trometry (MS), combined with specif-ically selected fragment compound collections, identify diverse, active low molecular weight fragments providing multiple highly efficient starting points for chemical optimi-sation.
tification of new starting points for SBDD programmes. Evotec offers both protein-observed NMR assays monitoring chemi-cal shift perturbations (SAR-by-NMR) as well as ligand-detected NMR assays (Saturation Transfer Difference (“STD”) NMR and Water LOGSY) for hit identi-fication. Hence, a broad range of target proteins amenable to NMR screening technique can be covered.
Evotec has employed its NMR screening platform on more than 30 protein targets covering a whole
Guided by high-quality data, SBDD at Evotec distils information into hypothesis-driven medicinal chem-istry. By minimising unnecessary and wasteful compound synthesis, productivity is increased and chem-istry teams are able to focus on an efficient path to the final drug.
Evotec has a comprehensive SBDD platform comprising state-of-the-art capabilities in: Computational chemistry Protein engineering X-ray crystallography Biophysical screening tools such as NMR, SPR, MS and ITC
FRAGMENT COLLECTIONSWe employ our collection of 20,000 fragments for biochemical, high concentration and SPR screening and a 3,000 fragment set for NMR screening all of which are optimally designed for quality, diversity and solubility at high concentrations to provide tractable starting points for optimisation within SBDD projects. The collection integrity is main-tained following validated processes used in our HTS collection to main-tain quality, diversity and novelty.
NMR SCREENING AND HIT QUALIFICATION
NMR screening as part of the Evotec FBDD platform is an alternative option for the iden- apo-protein Protein + fragment
range of target classes from frequently studied enzymes (like kinases or proteases) over nucleotide binding proteins or epi genetic targets, to protein-protein inter action targets, even receptor domains. NMR also adds con siderable value to biochemical screening campaigns by validating hit compounds for direct binding to the target protein and ultimately correlating this information to structure data, thereby enabling or facilitating SBDD programmes.
SURFACE PLASMON RESONANCE (“SPR”) SCREEN-ING AND HIT QUALIFICATION
Another powerful tool for study-ing biomolecular interactions in a sensitive and label-free manner in real-time is SPR. While commonly used at later stages of drug discovery projects to qualify hit compounds with regards to binding kinetics, the instrumenta-tion available at Evotec also allows for primary screening of frag-ments. Direct binding assays run on the Biacore™ 4000 screening device enable the identification of fragments interacting with immo-
bilised target proteins. As the throughput is sufficiently high, we are able to screen both fragment sets thus increasing the chance to find bona fide binders of the target.
Independent of the primary screen-ing strategy applied the assay tech-niques available at Evotec allow qualification of hits using alterna-tive read-outs. Here we typically combine the above mentioned approaches with orthogonal assays and technologies like Isothermal Titration Calorimetry (“ITC”), Differential Scanning Fluorimetry (“DSF”) and others.
STRUCTURAL BIOLOGYEvotec is located within a few miles of the UK’s third generation synchrotron and coupled with our own in-house X-ray source offers the ideal infrastructure for rapid cycle times in X-ray crystallography. The Structural biology team provides solutions to novel structure eluci-dation of drug targets and optimi-sation of crystal systems to support
industrialization of protein:ligand complex crystallography. Delivery of protein complexes is fine tuned across a project’s lifetime to main-tain the highest possible resolution while meeting the demanding cycle times of modern dis covery. Experi-ence covers the major target fami-lies with recent focus on crystallo-graphy of membrane proteins.
The team is co-located with the medicinal chemistry and compu-tational chemistry teams to maxi-mise interaction across integrated discovery programmes. The use of 3D virtual reality has provided the chemistry team with the ideal environment to understand and effectively mine structural infor-mation to focus synthetic strategies and rapidly progress optimisation. Working with innovative compu-tational scoring techniques, Evotec is experienced in maximising the value of structural information, providing foundation for rational design.
Aurora-B kinase inhibitor was developed alongside Roche with extensive structure-based design. Evotec employs multiple structure-based analytical tools to help prioritise compound ideas, alongside collaborative tools for communication with medicinal chemists
COMPOUNDMANAGEMENT
OFFERINGEvotec is uniquely qualified in deliv-ering its customers Compound and library management needs through over a decade of being the world’s leading compound management operation. Evotec expanded its oper-ational presence in 2013 by adding a second location in Branford CT which is strategically positioned to support the strong presence of Evotec’s drug discovery collaborators along the East Coast of the United States. Our service offering includes: Cost effective compound identifi-cation, selection, and procurement
High-throughput compound analysis Multi-format plating and reformatting
Inert atmosphere and low tempera-ture storage and processing
Fast order fulfilment and world-wide delivery
Multi-site disaster recovery and business continuity
“In-sourcing” of Evotec compound management staff to client sites
Our compound management experi-ence, primarily from the large Pharma and government sector means that Evotec understands its customers needs and deadlines. Each client has a dedicated Project Manager who provides a single point of contact to insure an open line of communication is always maintained.
COMPOUND IDENTIFICATION, SELECTION,
AND PROCUREMENTEvotec has extensive experience in the identification, selection and procurement of sub-collections of compounds possessing very specific (including commercial, physico-chemical or bioactivity-related) properties. Evotec has the capa-bility to apply compound identi-fication tools as required by the client.
Once compounds are identified for purchase, our Project Manage-ment group consults with selected suppliers to negotiate terms on behalf of our client requirements, e.g. price, purity and format. Evotec purchases compounds on a regular basis for a number of clients; therefore, the client can benefit from our vendor relations and volume discounts.
COMPOUND QUALITY CONTROL
Evotec typically uses a three-part incoming Quality Control (“QC”) process comprised of weight, solu-bility and LC-MS purity and iden-tity to ensure that all collections start with high-quality compounds. There are two Waters/Micromass 8-channel LC-MS systems, each with digital UV, evaporative light
Scott SnyderExecutive Vice PresidentCompound Management
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scattering (ELSD) and an LCT TOF mass spectrometer. These are high-throughput instruments with a capacity of 500,000 injec-tions per year. Evotec also offers ultra-high performance liquid chromatography with ELSD and electrospray mass spectrometry (UPLC-MS) method for quantita-tive determination of compounds in solution in DMSO.
COMPOUND STORAGEEvotec has invested in industry-leading automated storage systems and supporting informatics. Stor-age capabilities support vials, tubes, plates and bulk materials at controlled temperatures of -80°C, -20°C (inert atmosphere) and ambient. Actual storage condi-tions are dictated by sample type, containers and length of storage. Automated tube storage systems are equipped with high-speed pickers for fast arraying of tubes to support large plating campaigns and rapid follow-up. Evotec can also prepare a disaster recovery set of the client’s collection for stor-age at one of our other compound management facilities. This set can be readily accessed and processed for distribution at the client’s request.
COMPOUND DISPENSATION AND REFORMATTING
DMSO solutionsEvotec has the capability for auto-mated arraying of large numbers of compounds in DMSO between a large variety of containers suit-able for distribution or storage. Our extensive liquid handling resources cover the widest range of possible volumes.
High-volume end of the range are the eight channel pipettors, Tecan and Sias systems that can dispense and transfer 5 uL to multi-millilit-ers in vials and plates.
Middle of the range are the Agilent plate replicators (formerly VPrep and Bravo) that can dispense from 1 uL to 2 mL to and from 96, 384 and 1536 SBS format arrays
Low end of the volume range is the LabCyte Echo 550 that acous-tically dispenses volumes below 1 uL using multiples of 2.5 nL drops of solution
Neat compound dispensationEvotec has the capability to transfer neat samples via manual weighing, Volatile Solvent Trans-fer (“VST”) or Solvent Transfer methods.
COMPOUND SHIPMENTOur team has extensive experience in shipping chemicals, research compounds, controlled substances and reagents. Evotec delivers and receives compounds in all formats, both domestically and over-seas (including, but not limited to, North America, Europe and
DATA MANAGEMENTEvotec currently uses both a proprietary Compound Inventory and Tracking (“ComIT”) software system and the industry leading commercial application (Titian Mosaic) to manage, record and report all manipulations of client samples. These systems oper-
Asia). We are well-versed in docu-mentation requirements, tariff classification and import/export customs requirements. We have the ability to facilitate the import/export processes through the use of brokers as required by the Client.
Experts in Sample Logistics
> 44 million samples delivered to 377 recipients in 18 countries
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ate independent of each other at different sites but both deliver end-to-end functionality and traceability.
In support of our disaster reco-very and business continuity plans Evotec employs i365 Data Back-up and Recovery Solution to store incremental backups on a nightly basis and full server backups on a weekly basis. Data are transferred to two offsite locations automatically. All data transmissions are encrypted and password protected at all times for security and confidentiality.
QUALITY MANAGEMENTEvotec operates under the ISO9001:2008 Quality Manage-ment and internal auditing princi-ples but is not formally ISO9000 certified. We have well-defined and documented procedures to moni-tor and ensure the consistency of
EVOTEC TRACK RECORD Build and operate both private and public screening libraries since 2004
Largest individual library consists of ~490,000 compounds Over 25 client collaborations working to individual specifications > 44 million samples shipped to 377 recipients in 18 countries Over 4 million samples acquired and processed for clients Experience with 223 compound global suppliers
our output. Our process enables us to find defects early in the process and our procedures ensure correc-tive action is taken whenever a defect occurs, with the goal being to implement corrections with mini-mal impact to our final deliverables.
IN-SOURCING AND CONSULTING SERVICES
If a prospective client decides to retain compound management services within their operation then
Evotec also offers both in-sourcing and/or consulting services. In these instances, Evotec reviews require-ments with our clients and design solutions including need identi-fication, process design, facility layout, process workflow, vendor qualification and selection, and even complete staffing and management of onsite services.
Our in-sourcing program provides scientific staffing specifically designed to give clients the “non-permanent” workforce needed for anywhere from one year to multiyear partnerships. We hire, train and manage our employees to perform analytical scientific programs at client sites, using their quality systems. This advanced staffing model provides a non-permanent, long-term and cost-effective way to meet compound management staffing needs.
CHEMISTRY
OFFERINGSmall molecule drug discovery requires a deep understanding of biological context coupled to know-ledge and experience of the prop-erty space required to produce safe, efficacious drugs. Over the past 20 years, Evotec has developed exper-tise in numerous therapeutic areas including diseases of the central nerv-ous system (“CNS”), oncology, diabe-tes and metabolic diseases, pain, inflammation and anti-infectives.
We understand that each partner has different needs, internal capabilities and capacities. Evotec prides itself in being able to provide flexible, innova-tive and efficient solutions. Evotec’s experienced scientists can support your aspirations in a variety of ways. The capabilities listed below can be accessed individually where required or brought together to form complete project solutions: Cutting-edge molecular design Outstanding molecular model-ling and computational chemistry tools
Rapid synthetic execution In vitro ADMET, rodent PK and bioanalysis
Structural biology Expert advice on overall project strategy
Developing strategy for and securing IP protection
Project management
SYNTHESISAt the foundation of Evotec’s medicinal chemistry group is a talented and industry-experienced team of >150 synthetic organic chemists. Their skills are utilised during medicinal chemistry-driven projects, focused-library preparation and when preparing chemical building blocks or litera-ture compounds.
Synthetic execution is one of the most cost- and time-consuming parts of the early discovery process. We understand that where synthe-
sis is concerned, speed is para-mount. The faster our teams can deliver molecules into bioassays, the faster the project teams can obtain new knowledge.
Our approach is to employ, educate and retain talented chemists and to enable them with the latest tech-nology and equipment. More than 60% of our chemists are educated to PhD level
>40% of our chemists have >8 years experience at major pharmaceutical and biotech companies prior to joining Evotec
These facets enable Evotec to provide superior synthetic chemis-try and problem-solving capabili-ties to our partners and to deliver compounds in a shorter timeframe than our competitors.
Good molecular design often leads to complex syntheses (e.g. densely functionalised heterocycles, multi-ple chiral centres). Projects are successfully executed at Evotec that involve highly challenging synthe-ses and isolation procedures, for example: Natural products Steroids Macrocycles Nucleoside synthesis Sensitive pro-drugs
Dave HallettExecutive Vice President Chemistry Discovery Chemistry
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The origin of the chemistry department was in asymmetric synthesis and Evotec routinely develops enantioselective synthetic methods and has a full range of chiral separation technologies including SFC to deliver single isomers.
MEDICINAL CHEMISTRYEvotec has a powerful core of experienced, industry-seasoned drug hunters who drive the molec-ular design process. Collectively, this co-located group of medicinal chemists, computational chemists, structural biologists and DMPK
scientists has made significant contributions to discovery projects throughout their careers: >90 development candidates Named inventors and authors on >750 patents and publications
Our scientists are drawn from a variety of backgrounds and have been successful in all major ther-apeutic areas and target classes. Our teams are fluent and expert in both protein structure-guided and ligand-based design.
The focus of our medicinal chemistry teams is on high-quality
design and crisp decision making. The process at Evotec is enabled by widespread availability of visualisation, analysis and design software tools. Our medicinal chemists target analogues within defined property space to answer specific structure-property and structure-activity questions – the emphasis is always on making the right compounds with opti-misation of biological activity and a properties in parallel. We firmly believe that the co-location and interaction of synthetic and medicinal chemistry, computa-tional science, structural biology and DMPK enhances the overall design, analysis and communica-tion process: More learning cycles per unit time = more knowledge and experience = better quality output
More informed decisions = less waste
An example of multiparameter optimisation. Evotec’s design teams simultaneously improve physicochemical properties as well as biological activity. The plot above (-log10IC50 versus calculated LogD) highlights three different chemotypes from the same project. Over 2 iterations, the arrows indicate the improvements made to each series as seen from the improved Lipophilic Ligand Efficiency (“LLE”) scores
0 1 2 3 4 5
4
9
8
7
6
5
plC50
Series Aplc50 5.45LLE 3.16clogD 2.3
Series Bplc50 5.58LLE 2.9clogD 2.7
Series Cplc50 7.19LLE 3.78clogD 3.4
Series Cplc50 7.29LLE 4.02clogD 3.3
Series C analogueplc50 6.97LLE 4.65clogD 2.3
Series B analogueplc50 6.62LLE 4.1clogD 2.5
Series A analogueplc50 6.8LLE 5.3clogD 1.5
cLogD
LiPE2
LiPE3
LiPE4LiPE5LiPE6
COMPUTATIONAL CHEMISTRYEvotec’s Computational Chemistry group comprises 10 PhD molecu-lar modelers working with both commercial and in-house developed software tools.
The members of this group come from diverse backgrounds and through close interactions within project teams they provide unique insights and input across the whole discovery process: Virtual screening (X-ray structure, homology and ligand-based)
Multi-parameter (“QED”) analy-sis of private, commercial and virtual compound sets
Construction and refinement of structure-activity and structure-property relationships
Proprietary suite of GPCR modelling tools
Execution and graphical visu-alisation of complex quantum-mechanical calculations which highlight to Evotec’s medicinal
chemists the components that contribute to binding in protein-ligand complexes (Fragment molecular orbital analysis)
Creation of electronic workflows for our teams (e.g. Knime) to provide our chemists with desk-top access to complex computa-tional methods
DRUG METABOLISM AND PHARMACOKINETICS (“PK”)
Evotec offers a comprehensive and flexible range of in vitro ADME and PK services designed to cover the majority of activities in the screen-to-candidate phase. The scientific expertise and assays are accessed in a variety of ways by our clients and project teams: Stand-alone profiling
— Automated, medium through-put assays (100s of compounds per week)
— Tailored packages designed to address a specific compound or problem
Routine testing (e.g. weekly) and expert interpretation of data within integrated medicinal chemistry teams
Evotec’s combination of routine in vitro assays and our flexibility to address your individual require-ments enables us to offer a truly bespoke service – experienced DMPK scientists delivering data of the highest quality coupled with a cost effectiveness afforded by highly automated procedures.
STRUCTURAL BIOLOGYEvotec’s crystallography group comprises a team of 8 skilled crystallographers together with state-of-the-art-infrastructure to support protein production and purification to the high standard required for this biophysical tech-nique. The groups’ collective experi-ence covers the major target families with a recent focus on crystallog-raphy of membrane proteins. The
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group benefits from a unique geog-raphy; co-located with the medici-nal chemistry and computational chemistry groups at Evotec as well as being <5 miles from the UK’s national synchrotron (Diamond). When discovery projects are fortu-nate to be structurally-enabled, Evotec’s crystallographers form an integral part of the molecu-lar design team. As a result of this, they are acutely aware of the rapid cycle times required if novel protein-ligand complexes are to make a meaningful contribution to the design process. Delivery of protein complexes is flexibly allo-cated across a project’s lifetime to maintain the highest possible reso-lution while meeting these demands.
Evotec’s expertise in medicinal chemistry has enabled it to success-fully execute collaborations with a broad range of partners from academic institutions through to large pharmaceutical companies.
EVOTEC TRACK RECORD Over the last 15 years, Evotec chemists have supported >125 hit-to-lead and/or lead optimisation projects
Evotec scientists are named inventors on >200 client patents and have helped identify >30 pre-clinical candidates
Our project teams have made major contributions to the identification of >20 compounds that have been approved for clinical trials
OFFERINGIn the pharmaceutical industry, early liability assessment of drug candidates is an important element to decrease the high attrition rate in the drug discovery and development process. One of the key challenges is the balance between drug efficacy and potential adverse effects at the earliest possible point in time for de-risking cost-intensive activities especially during late-stage clinical development.
To meet this demand Evotec has established an industrialised high-throughput ADME profiling service for routine compound screening against a panel of the most criti-cal safety pharmacology targets. Potential drug-drug interaction can be determined by using our panel of cytochrome P450 (“CYP450”) reversible inhibition (“RI”) assays for the six main CYP450 isoforms in combination with time-dependent inhibition (“TDI”). Furthermore,
drugs can be identified activating the human pregnane X receptor (“PXR”) to induce CYP450 3A4. Additional critical ADME assays identify inhibi-tors of the hERG, Nav1.5 or Cav1.2 ion channels which are implicated in adverse cardiovascular events.
ADME assays for four highly relevant CYP450 isoforms are established on our high-throughput RapidFire/MS platform. Medium-throughput LC/MS/MS based assays are provided for CYP450 1A2 and 2C19.
In support of discovery chemis-try programmes, externalization of safety pharmacology profiling is providing a unique business oppor-tunity for our partners to reserve internal capacity for core research activities, expand their ADME assay portfolio and to mitigate risk. Besides these benefits high-through-put ADME profiling is a time- and cost-efficient process consistently
ADME ASSAY READ-OUT THROUGHPUT COMPOUNDS/WEEK
CYP450 3A4, 2C8, 2C9, 2D6 (RI) RapidFire/MS >800
CYP450 2C8 (RI) RapidFire/MS >300
CYP450 1A2, 2C19 (RI) LC/MS/MS >150
CYP450 3A4 (TDI) RapidFire/MS >600
CYP450 3A4 (induction of PXR receptor) Luminescence >600
hERG Radioligand binding >800
hERG Ion Works® Quattro™ >100
Nav1.5, Cav1.2 FLIPR™ >800
Portfolio of high-throughput ADME Profiling assays
Joachim KraemerSenior Vice President Bioreagents, Biophysics and Assay Development
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(1) A lysate of the cell line or tissue of interest is prepared. (2) A matrix comprising of immobilized broad-spectrum kinase inhibitors is used to enrich the expressed kinome of the cell or tissue sample. (3) Competition assays with the free test compound and (4) quantitative mass spectrometry analysis reveal the compound’s affinity profile, (5) ranking all protein kinase targets according to their Kd values for the free compound.
Sepharose resinImmobilised kinase inhibitortest cpdTarget kinaseTarget kinase bound to test cpd
1 Cell or tissue sample
2 Mixture of beads of broadly selective kinase inhibitors for enrichment of kinases
3 Competition of target kinases by test compound
Test compound
4 LC-MS analysis 5 List of target kinases ranked according to their Kd values
platforms. Ion channel electrophys-iology assays run on Ion Works® Quattro™ automated patch clamp platform
Flexible data analysis with internal or external software tools enabling rapid data uploads
Professional project management with experienced leads
KINAFFINITY®
COMPOUND PROFILINGNumerous small molecule kinase inhibitors are currently being devel-oped for treatment of cancer, inflam-mation or autoimmune diseases. However, drug discovery faces significant challenges, particularly due to unacceptable safety pharma-cology profiles caused by an inhibi-tor’s lack of selectivity. Undesirable off-target kinase profiles frequently induce toxicity that might halt the development of candidate drugs. To decrease the high attrition rate the design of selective as well as multi-specific inhibitors is becoming increasingly important.
KinAffinity® is Evotec’s hit-to-lead compatible approach to profile drug
delivering highest data quality. Pharmacological sensitivity and statistical robustness of the ADME assays is routinely monitored by a range of reference compounds
ADME assays are performed according to validated SOPs and provide 8-point IC50/EC50 for test compounds in triplicate
Turnaround time from compound reception to data reporting is 7 working days
Assays are scalable towards higher throughput
TECHNOLOGY PLATFORM AND EXPERT KNOWLEDGE
Within many collaborations with major pharmaceutical and biotech companies, Evotec has successfully provided expert knowledge in devel-opment and integration of complex processes for our collaborator’s drug discovery programmes including: Logistics of compound shipments in close interaction with global carriers
Management of large libraries and regularly shipped smaller compound batches for ADME or SAR profiling
Broad expertise in assay devel-opment with > 400 biochemical, biophysical and cell-based assays
Compound profiling using bench-top and fully automated screening
candidates against endogenously expressed, full-length proteins in the presence of cellular co-factors and native complex partners – a major advantage over traditional biochemical panel screening using only recombinantly expressed, purified proteins or protein domains. Evotec’s platform: Enables rapid target profiling of kinase inhibitors in cell and tissue samples. Unlike traditional biochemical kinase panel screen-ing, the inhibitor’s target affini-ties are determined simultane-ously for a large number of native kinases within their physiological cellular environment
Identifies target interactions possi-bly requiring additional co-factors or the formation of multi-compo-nent complexes, thereby comple-menting traditional biochemical assays that use only recombinant proteins
Can determine a target’s Kd value to a free compound without need-ing to immobilise the inhibitor
Employs a ready-to-use affinity matrix comprising well-charac-terised broad-spectrum kinase inhibitors to enrich the subpro-teome of endogenously expressed kinases of cells or tissues
PROTEOMICS
Henrik DaubSenior Vice President Chemical Biology
OFFERINGEvotec offers unique proteomics services to address key issues in drug and biomarker discovery. We contin-uously advance our capabilities in mass spectrometry-based proteom-ics to ensure unrivalled compre-hensiveness and data quality when analyzing cells, animal models and patient samples.
This involves: Highly optimised experimen-tal strategies tailored to differ-ent proteomics applications and project needs
Industry-leading capabilities in high-end quantitative mass spec-trometry
Experience and infrastructure to analyse the enormous amounts of data generated in large-scale
proteomics projects Advanced statistics and bio-informatics for systems-wide data analysis
In-depth data interpretation to extract relevant drug target and mode-of-action information from proteomics experiments
Extensive track record to deliver high-quality results within agreed timelines
Evotec’s chemical proteomics methods such as Evotec Cellular Target Profiling™ reveal cellular drug targets and selectivity in an unbiased manner. Other Evotec proteomics technologies record protein modification and expres-sion on a proteome-wide scale for drug mode-of-action analysis or biomarker discovery efforts. Thus,
PhI/IIPre-clinicLOH2LScreeningTarget ID & validation
EVOTEC CELLULAR TARGET PROFILING™
TO SUPPORT H2L
TARGET DECONVOLUTION
CELLULAR MODE-OF-ACTION ANALYSIS TO SUPPORT LO
DRUG REPOSITIONING
PROTEOMIC SIGNATURES FOR BIOMARKER DEVELOPMENT
TARGET DISCOVERY
MODE OF ACTION ANALYSIS
RESPONSE PREDICTION
BIOMARKER ASSAYS
HT SCREENS/ SCAFFOLD SELECTION
ON/OFF TARGET PROFILING
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quantifying target binding across defined sets of affinity purifica-tion and drug competition experi-ments.
Evotec Cellular Target Profiling™ Reveals and verifies specific cellular targets of a drug by quantitative mass spectrometry
Determines target-specific dissociation constants for the compound studied, ranking targets according to their likely physiological relevance
Performs selectivity analysis on a proteome-wide scale against native, post-translationally modified proteins in the pre-sence of cellular co-factors and complex partners
Has an extensive, non-target class restricted track record in
our platform offers highly innova-tive solutions that can be leveraged across the entire drug discovery and development pipeline.
QUANTITATIVE CHEMICAL PROTEOMICS
Evotec scientists have pioneered chemical proteomics applications for the identification of cellu-lar small molecule targets. The basic concept involves functional immobilisation of an appropri-ate linker derivative of a drug, followed by affinity purification of target proteins from cell or tissue extracts and finally their identifica-tion by MS analysis. Unlike other competitor technologies, our Evotec Cellular Target Profiling™ technology captures target speci-ficity and affinity information by
successful profiling of diverse small molecule compounds
Selectivity data about cellular on- and off-target liabilities is particu-larly useful to inform decisions at various stages of drug development, for example in the lead optimisation phase or in the pre-clinic candidate selection process. Moreover, chemi-cal proteomics enables target decon-volution of bioactive compounds identified in phenotypic screens. Cellular target identification is the crucial step to enable further drug optimisation and development. Evotec Cellular Target Profiling™ perfectly complements Evotec’s medicinal chemistry and high-content screening capabilities to deliver new drugs and targets across many therapeutic areas.
Evotec Cellular Target Profiling™ key elements
(1) A lysate of the cell line or tissue of interest is prepared. (2) A linker derivative of the test compound is immobilised on sepharose beads and used to enrich compound target proteins. (3) Competition assays with the free test compound and (4) quantitative mass spectrometry analysis reveal the compound’s affinity profile, (5) ranking all protein targets according to their Kd values for free compound.
Sepharose resin
Linker derivative of test cpd
test cpd
Target proteins
Test compound
1 Cell or tissue sample
2 Enrichment of target proteins by compound affinity chromatography
3 Competition of target proteins by test compound
4 LC-MS analysis 5 List of target proteins ranked according to their Kd values
GLOBAL ANALYSIS OF PROTEIN MODIFICATIONS
Evotec’s proteomics platform for global protein modification analy-sis permits the identification and quantification of more than 10,000 phosphorylation sites, 1,000 lysine acetylation sites or 5,000 ubiquit-inylation sites in a single experiment, which may be performed in cells, tissues or patient samples. Accurate quantification is enabled by differ-ential isotope labelling, while highly optimised peptide enrichment and analysis on fast, sensitive and accu-rate mass spectrometers ensure highest coverage. Evotec’s platform provides highly reliable results, both for in-depth bioinformatics involv-ing enrichment, cluster, network and motif analyses, as well as for expert data interpretation on the level of site-specific changes.
Our quantitative phosphoproteom-ics (PhosphoScout®) enables the
unbiased and comprehensive inves-tigation of signalling pathways, to delineate the cellular modes of action for kinase inhibitors. Typical applications include: Identification of specific pharma-codynamic read-outs for thera-peutic kinase inhibition
Selection of lead compounds or pre-clinical candidates with maxi-mal on- and minimal off-target activity in cellular conditions, either as single agents or in combi-nation with other drugs
Monitoring phosphoproteome regulation in different biological models to shed light on factors underlying differential biological activity of lead compounds or pre-clinical candidates
In addition to PhosphoScout®, Evotec’s acetylomics and ubiquitin-omics platforms offer similar appli-cations for HDAC and E3 ligase inhibitors using highly optimised
workflows with regard to sensi-tivity and selectivity. As a result, these technology platforms enable comprehensive mode of action studies in the biologically relevant context.
GLOBAL PROTEOME PROFILING AND BIOMARKER
DISCOVERYEvotec offers industry-leading plat-forms for comprehensive protein expression profiling allowing un- biased, proteome-wide target and biomarker discovery on the func-tional protein level. Depending on the application and required throughput, tailored proteome anal-ysis workflows are available:
Deep proteome profiling for de tection of up to 10,000 proteins from cell or tissue samples upon efficient peptide pre-fractionation
Single-shot proteome profiling to a depth of 5,000 proteins in cell or
PhosphoScout® Workflow
Isotope labelling
Proteins Peptides Global phosphoproteome enrichment LC-MS
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tissue lysate, enabling compara-tive proteome analysis across 100+ samples
Comprehensive analysis of any type of biological material, including formalin-fixed paraf-fin-embedded (“FFPE”) solid tumor samples and body fluids such as plasma and CSF
Targeted mass spectromety anal-ysis by Multiple Reaction Moni-toring (“MRM”) fully established at Evotec for follow-up validation experiments
Both the expertise and the data processing infrastructure are in place for accurate quantification across many different samples, such as whole panels of cell lines, xenograft models or patient tissue samples. Such data, together with drug response information, provides a unique basis for the discovery of predictive protein biomarkers, argu-ably one of the most exciting prot-eomics applications in future medi-cine.
Pre-clinical biomarker discovery in animal models
Unbiased biomarker identification from mouse xenograft models by global and targeted proteome analysis
Clinical biomarker in patient samples
Proteome-wide biomarker identification from patient-derived leukemia cells or FFPE tumor tissue
Early identification of predictive biomarker candidates by proteome profiling of cell line panels
Pre-clinical biomarker discovery in cultured or primary cells1
2
3
LC-MS Data analysis
EVOTEC’S THREE-TIER STRATEGY TO SUPPORT ONCOLOGY BIOMARKER
DISCOVERYEvotec technologies cover the entire biomarker discovery phase including elaborate bioinformatics for the iden-tification and verification of predic-tive multivariate markers, so-called protein signatures. These capabilities have been demonstrated in various cancer-related projects, delivering response prediction signatures in lung cancer cell lines, mouse xeno-graft models and leukemia patients.
In conclusion, Evotec offers an integrated and unique platform of innovative proteomics technolo-gies for drug and biomarker discov-ery. Moreover, Evotec is constantly investing in R&D activities dedi-cated to advance its high-end prot-eomics capabilities and maintain industry leadership in the years to come.
OFFERINGEvotec provides access to a comprehensive base of services and capabilities around cell and protein production. These can be accessed as a stand-alone function or as an integral part of a wider collaborative programme accessing our drug discovery expertise. Combining expertise in cell culture and protein production methods with expertise in
There are numerous reasons why a target may not be stably expressed in mammalian cells and a transient approach may be more appropriate for cell-based screening. To address this problem, Evotec routinely uses a variety of transfection technolo-gies from lipid based to viral medi-ated delivery to achieve transient expression.
Particularly the MaxCyte electropo-ration platform offers access to large batches of up to 10 billion cells, a cost-effective and efficient trans-fection process. Transiently trans-fected or virus transduced cells can be provided as assay-ready frozen instant cells, which are functionally expressing the target instantly after thawing.
The availability of cells is a critical bottleneck in screening campaigns. Frozen instant cells, which can be assayed without prior cultivation have become a valid and frequently used alternative to cells from a continuous growing culture.
Evotec’s cell culture unit was one of the first suppliers of frozen instant cells for global pharmaceutical research. Cells are: Expanded under controlled culture conditions to large bulk quantities
Harvested applying a gentle
CELL & PROTEINPRODUCTION
Mark SlackVice President In vitro Pharmacology
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functional assays, assay development, HTS and compound profiling offers clients the best-possible platform for cost-efficient and timely delivery of highest quality data for their drug discovery programmes.
Evotec’s wealth of expertise covers all principles including cell line generation, small- or large-scale transient transfection, frozen cell technologies and protein expression from small-scale proof-of-concept studies through to batch production for HTS, counter screening activities as well as structural biology applica-tions. For clients looking to outsource the management and supply of their own cell collections, Evotec offers a cell bank management scheme, establishing, propagating and distrib-uting thousands of cell lines between various locations.
CELL LINE GENERATION AND BANKING
From recombinant cells which have been either generated by stable transfection or viral transduction, monoclonal cell lines are isolated and screened for their functional expression of the target protein. After a first broad screening on expression level using immuno-fluorescence labelling, Westernblot, or RT-PCR, usually a secondary screening of selected clones by a cell-based assay is applied.
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Cell line generation(n=59 projects)
Transporters 4Reporter cell lines 3
Others 9
GPCR 23
Ion channel 7
Enzymes 3
Kinases 4
NHRs 1
Cytokine receptors 5
Transient transfections(n=56 projects)
Others 17
Ion channel 9
GPCR 13
Enzymes 2
Proteases 13 Transporters 2
Assay ready frozen cells(n=223 projects)
Transporters 18
Primary cells 10
Others 35GPCR 96
Ion channel 46
Kinases 8
NHRs 10
method which does not affect surface receptors
Prepared to a density which corre-sponds to the requirements of your assay, the cells are dispensed into vials using an automatic fill-ing device. This fast processing of the cells significantly decreases the time from harvest to freezing, which is critical for maintaining the quality of frozen instant cells
Frozen in a controlled rate freezer and stored at -150°C until they are shipped to you
For secondary screening or drug profiling, in which you need only a few assay plates per day over a longer period of time, we can apply a proprietary technology to freeze cells directly in assay plates which can then be used upon demand. For ligand binding assays, we offer cell membranes in bulk.
All batches of cells and cell-based products are carefully controlled for their quality before they are shipped to you. Frozen instant cells are checked not only for viability but also for their ability to adhere shortly after thawing. A good „fitness“ of the cells is often corre-lated with fully functional response. Finally, the assay performance of the frozen cells is compared to cells from a continuous growing culture considering Z’, S/B and EC50.
Membranes(n=40 projects)
Others 5
Ion channel 10
GPCR 19
Transporters 6
including the labelling of proteins for NMR and mass spectroscopy, material for SPR and ITC and crystal grade material for macro-molecular X-ray crystallography. The production platform deliv-ers on hundreds of recombinant
proteins for drug discovery per year to our clients.
Established work-flows for all major activities involved in protein production lead to routine and
reproducible results. Our highly experi-
enced team of scientists will optimise expression levels
and purity using a suite of tech-niques, including semi-automated expression analysis and purification, to guarantee quality in a realistic timeframe.
Evotec offers professional manage-ment and maintenance of client cell banks encompassing the addi-tion of new cell lines and shipment of assay ready cells and vials to the client’s research centres. A dedi-cated team with access to the neces-sary bioinformatics, quality control processes and infrastructure can additionally provide support in the sourcing and maintenance of disease relevant cell banks such as oncology. The databases covering all aspects of the respective cell line such as growth rates, morphology and genetic confirmation are avail-able over a web-based client portal providing clients with the essential access to all necessary information.
Construct design
Quality
Cloning & expression
Protein purification
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RECOMBINANT PROTEIN PRODUCTION
Protein production lies at the heart of drug discovery. Evotec’s recom-binant protein production facilities provide comprehensive coverage of expression hosts, purification tech-niques and analysis tools and delivers a unique solu-tion for the efficient delivery of high-quality proteins in a timely fashion. Our capabilities can be accessed flexibly, either as standalone units or as part of an integrated drug discov-ery programme.
All proteins are prepared with end use in mind, including the delivery of high-quality proteins for bio-assay and biophysical applications
DNA engineering
Stably transfected cells
Frozen instant cells
Custom cell & reagent supply
Transiently transfected cells
Bulk cell production
Membrane preparation
Non transfected cells
Recombinant proteins
Evotecs screening services
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E. coliup to 120L/week
Tags: no tag, His (N- or C- terminal), GST, MBP, Trx Strains: BL21 (DE3)/pLysS, ArcticExpress, BL21-AI Secretion signal peptide (if needed): pelB
Tags: no tag or C- terminal His-tag Strain: X-33 Secretion signal: α-Factor
Pichia pastorisup to 20L/week
Tags: no tag, His (N- or C- terminal), GST, MBP Strains: Sf21, Sf9, T. ni Secretion signals (if needed): gp67, honeybee
melittin, wild type
Insect cells (Baculovirus)up to 80L/week
Tags: no tag, His (N- or C- terminal), GST, MBP Strains: CHO, HEK293, CAP-T Secretion signals (if needed): wild type, lgk
Mammalian cells up to 30L/week
Expression hosts in 2013, >400 production runs completed
NMR 3%
Mammalian 14%
Other 2%
Pichia pastoris 1%
Crystallo 58%
E. coli 48%
Assays 37%
Insect cells 37%
Uses of protein
Specific expertise in the team covers the common protein fami-lies and also extends into the more demanding areas of macromo-lecular complexes (protein:protein and protein:DNA) and membrane proteins.
All main expression hosts are supported by Evotec with shut-tle vectors available to rapidly move expression to higher organ-isms as required. Gene synthesis is performed by a series of secure third party relationships with confirmed timelines.
The team has unparalleled expe-rience in labelling of proteins for NMR work including ubiquitous 15N, 13C and 2H in E. coli and yeast and side chain specific labelling in insect expression hosts.
In addition to purification of proteins by SOPs or according to literature precedents, Evotec has extended methods commonly employed in structural genomic facilities so that the team can perform High-throughput (“HTP”) expression screening in E. coli, insect and mammalian hosts to determine opti-mal conditions for production ahead of large scale production runs. Large scale expressions can be carried out in parallel, either in shake flasks or in eight WAVE cellbag bioreactors, each capable of producing up to 25-L of material for purification.
With fifteen Akta purification modules and HTP methods suit-able for cost-effective paralleliza-tion, Evotec has the capacity to deliver significant quantities of proteins in realistic cycle times through a variety of purification schemes (see figure above).
All proteins pass stringent in process quality controls, selected from a panel of options includ-ing Mass Spectroscopy, Dynamic Light Scattering, Differential
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Three example methods for HTP purification are shown. Either single step IMAC columns run by gravity (Method 1) or on an Akta Xpress (Method 2) or a two-step process on Akta Xpresses (Method 3) may be performed
IMAC His-Trap (Akta Xpress)
SEC
Insufficient yield
Option 3 – 8/week
IMAC His-Trap (Akta Xpress)
Insufficient yield
Option 2 – 16/week
m/z m/z
SDS-PAGE, Western blotting, M.S.
QC
Yes
Further scale-up/ optimisation
e.g. 10-20L, as desired
DispatchYield and quality OK?
Option 1 – 24/week
Insufficient yield
IMAC His-Trap (Gravity)
No
Scanning Fluorimetry, Activ-ity Testing and NMR, before final release to the end user. In summary, by tailoring the purifica-tion schemes to the problem to be solved and using appropriate input from scientists on the projects, Evotec delivers the target protein optimised for the end use.
Driven by demand the reagent production team will be expand-ing in 2015. At the end of March 2015 a new facility in Princeton, US will be operational across cell science and recombinant protein production. This facility will deliver the range of high quality services currently offered from our European sites, but will be able to provide the fastest possi-ble cycle times for business critical deliveries.
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SDS-PAGE Co2+ IMAC
Western Blot Co2+ IMAC
Crystals
A2a receptor purification using cobalt IMAC at Evotec (left and center) yields sufficient protein for crystallisation by the lipidic cubic phases (LCP) technique
LABELLING CHEMISTRYEvotec offers labelling of biologi-cal relevant molecules and reagents for use in ELISA, FACS, FCS, plate readers and other fluores-cence based detection systems. Our service helps clients to improve their research results in all areas of biological and pharmacological assays, as well as clinical diagnostics and analytics. Our expertise covers the labelling of the following: Small organic molecules e.g. hormones, neurotransmitters
Peptides and chemokines (as enzyme substrates, GPCR ligands, etc.)
Proteins including antibodies Site-specific mutagenesis of proteins (for site-specific labelling)
Glycoproteins
Carbohydrates Lipids (for membrane studies) Beads and surfaces
Evotec’s labelling chemistry team has acquired a comprehen-sive expertise having successfully designed and labelled components for more than 150 different assays representing a broad range of assay classes. For labelling we use the optimally suited dyes and tags for your application, such as: Proprietary dyes (EVOblue™ family)
Commercially available fluores-cent dyes and the in-licensed MR121 dye
Non-fluorescent markers and probes like affinity tags, biotin, reporter enzymes, etc.
OFFERINGThe cornerstone of Evotec’s in vitro pharmacology function is disease and target biology expertise coupled with state-of-the-art technology platforms. A large team of scientists with extensive industrial experience supports the in vitro pharmacologi-cal characterisation of compounds as part of hit expansion, lead finding or lead optimisation projects. Our team routinely generates project-relevant high-quality data in short turnaround times.
Typical activities include: Development of biochemical and functional assays
Secondary and tertiary charac-terisation of screening hits
Compound characterisation as part of hit-to-lead and lead opti-misation programmes:
— Design and implementation of target-relevant assays (screen-ing cascades)
— Potency and selectivity testing— Mode of action studies (e.g.
competitive versus allosteric mechanisms, reversibility, use-dependent mechanisms for ion channel modulators)
— Translational assays: testing of compound potency and mech-anism using disease-relevant primary cells from rodents, primates or human
In more than 15 years of compound profiling at Evotec, >400 assays have been developed and executed. Such activities are part of Evotec’s integrated lead finding and optimisation projects but are also frequently used to support medici-nal chemistry projects that are executed in the labs of Evotec’s partners.
AVAILABLE READ-OUT AND ASSAY TECHNOLOGIES
Evotec has access to a wealth of assay technologies that can be utilised to assess compound activ-ity. Appropriate technologies and expert teams are selected to answer key project questions and to ensure project advancement. Beyond standard and established read-out technologies for biochemical and cellular assays, Evotec has built key expertise in a number of tech-nological areas that have shown to
BIOPHYSICAL READ-OUT TECHNOLOGIES Surface Plasmon Resonance/SPR Mass Spectrometry/LC/MS Nuclear Magnetic Resonance/NMR Radiometric Thermal Shift ELISA
Neuroprotective compound
be drivers for the success of our partner’s projects. These include: The use of stem cells to derive neurons and primary neuronal cultures to build disease-relevant cellular models and to identify and characterise new compounds with disease-modifying properties
An extensive knowledge of high-content screening and a state-of-the-art hardware platform to run complex and disease-relevant imaging assays, e.g. using primary neuronal cultures, kidney cells as well as rodent and human beta cells
A world-leading ion channel discovery platform including fluo-
rescence-based assays, automated and manual patch clamp methods
An excellent suite of bio physical methods including SPR and NMR that are utilised as part of our structure-based drug design projects but also LC-MS-based methods that are utilized to assess difficult-to-assay enzyme targets
OVERVIEW TARGET CLASSESOur in-depth experience in the biol-ogy and pharmacology of disease-relevant target classes is what our partners come to us for. This exper-tise is a key driver to the successful and rapid execution of lead finding and optimisation processes. Evotec’s in vitro Pharmacology team has gained expertise across a wide area of disease targets. Beyond a large number of projects that have success-fully been run in the classical target areas such as GPCRs, ion channel and kinases, we have also worked on a large diversity of other target areas such as transporters, protein-protein interactions and multiple enzyme families, including novel target classes such as epigenetic regulators.
DISEASE EXPERTISE AND TRANSLATIONAL ASSAYS
Evotec’s core expertise includes areas such as CNS, neurodegenera-
tion, pain, inflammation, metabolic disease, oncology and immunology. Our scientific expertise and under-standing of disease mechanisms combined with our track record in setting up relevant in vitro models is a key factor in our success when working with our partners.
Co-culture system of stem cell derived motoneurons and astrocytes together with microglia to identify cpds for the treatment ALS
Identifying cpds that protect podocytes in chronic kidney disease
SECTION 9
Setting up complex in vitro assays utilising rodent or human primary cells to confirm the potency and mechanism of lead compounds is a prerequisite to build confi-dence in the translatability of any mechanism. We build these assays early in the drug discovery process to gather disease-relevant data before assessing compound efficacy in vivo. Such assays are also utilised to identify read-outs for in vivo target engagement. We routinely utilize various neuronal and stem cell cultures, pancreas and beta cells, kidney cells and various immune cells to assess bespoke read-outs and mecha-nisms, including cell health and survival, apoptosis, differentia-tion, de- / regeneration; neurite outgrowth, retraction and synap-tic density; cellular signalling and secretion.
D3 After PlatingDays After Plating
Neur
ite To
tal L
engt
h
GFAP/GFP/DNA
2 3 4 5 6 7
100K
80K
60K
40K
20K
39
Extensive expertise with translational assays using primary cells and tissues to investigate compound potency and mechanism
ISOLATION, CULTIVATION AND MANIPULATION OF PRIMARY CELLS Neurobiology: neurons (CNS, DRGs, moto-neurons), astrocytes, microglia including co-cultures
Cytokine secretion Transcrptional activity Protein phosphorylation
ASSAY TECHNOLOGIES Imaging MSD LC-MS Standard methods
Human kidney cell fibrosis Replicating pig beta cells
Rodent glomeruli Synaptic connectivity
OFFERINGEvotec’s world-class ion channel platform combines industry-driven expertise with state-of-the-art instru-mentation. In routine use are multi-ple setups for manual patch clamp studies and all of the most popular automated patch clamp instruments. The automated patch clamps or FLIPRs can be used as entry points for HTS, and the manual and auto-mated patch clamps enable on-going support of medicinal chemistry programmes progressing from HTS through hit expansion, hit-to-lead, lead optimisation but are also utilised for safety pharmacology.
OVERVIEW OF ION CHANNEL SCREENING AT EVOTEC
Evotec has a strong background in running hit identification campaigns against ion channel targets. On average more than 235,000 compounds per target are screened in singlicate at a fixed compound concentration. Campaigns resulted in “primary” hit rates in the range of 1% and confirmation rates are generally good (>50%), underlining robust assay performance. Second-ary assays using electrophysiology to confirm compound activity is part of the routine HTS follow-up and are key to the successful iden-tification of relevant starting points for medicinal chemistry projects.
Port-A-Patch® 2 1-well 25-50 Hit-to-Lead, Lead optimisation
Manual Electrophysiology (Dynaflow™ optional)
5 1-well 1-25 Lead optimisation, safety pharmacology
IonWorks® Quattro™ Qpatch HTX® PatchLiner® Dynaflow® Pro II Manual Patch-Clamp
The electrophysiology platforms in place at Evotec
Stephen HessResearch Leader Ion Channels
SECTION 10
41
Voltage-gated sodium channels (NaV) are expressed in neurons The selective NaV blocker, TTX (300nM) inhibited NaV signal in big diameter cells (arrows)
Ligand-gated ion channelsP2X family (e.g. P2X3, P2X7)Glutamte receptors (e.g. NMDA, AMPA)TRP family (e.g. TRPV1, V3, V4)GABA-A
Voltage gated ion channelsPotassium ion channels: Kv familyCalcium channels: Cav familySodium channels: Nav family
1
2
3
OthersCRACChloride channel (e.g. CFTR)4
EXPERTISE IN IDENTIFYING CHANNEL OPENERS AND BLOCKERS
DEMONSTRATED CAPABILITY IN ION CHANNEL DRUG DISCOVERY ACROSS VARIOUS PLATFORMS FROM 1 TO 384 WELL FORMAT
TRACK RECORD OF SUCCESS WITH A RANGE OF
ION CHANNEL CLASSES Evotec has electrophysiology and ion channel pharmacology expertise using transiently- &
stably-expressing cell lines or cells from primary tissues (e.g. DRGs, NDGs). In addition, we have capabilities and experience in the generation of transient and stable formats for ion channel targets.
NDG neurons 6h after preparation NaV current
TTX 300nM
NaV channel
X: 1.00 ms Y: 2.00 nA
Electrophysiological recordings from primary cells provide addi-tional mechanistic insight beyond that possible using recombinant cells. In this case we used neurons isolated from dorsal root and nodose ganglia. On the right is an example taken from our efforts using mouse nodose ganglion neurons:
OFFERINGAnimal models remain crucial for providing a holistic understanding of how drugs work in vivo. Evotec offers in vivo pharmacology services following custom-designed protocols to support your drug discovery needs from delivering single studies to taking over responsibility for planning the in vivo pharmacology strategy of integrated drug discovery programmes. Evotec’s in vivo phar-macology team consists of highly experienced scientists with extensive pharmaceutical and biotechnology backgrounds. Evotec has state-of-the-art animal facilities equipped to house immune-compromised animals, genetic models and other rodents. All experimental procedures involving animals are approved according to EU and federal law.
Evotec develops bespoke assays to support drug discovery programmes to drive Structure–Activity Rela-tionship (“SAR”) and development of PK/PD relationships. We further offer high-quality in vivo services including target validation, toler-ability studies, efficacy screening, in vivo pharmacology profiling and mode-of-action (MOA) studies in a wide range of therapeutic areas.
METABOLIC DISEASEModels include type 2 diabetes, obesity and beta-cell regeneration
Models: fa/fa- and ZDF-rats, db/db-, ob/ob- mice; Diet-Induced Obesity (“DIO”) mice; Ins2-Akita mice; Chemically-induced diabe-tes using STZ/Alloxan in rodents (neonatal and adult)
Read-outs Body weight, food intake and water consumption
Models: transgenic mice and rats for Chorea Huntington and mice for Alzheimer’s disease.
Read-outs Locomotor activity (rotarod), emotion (Elevated Zero Maze, fear conditioning), cognition (Novel Object Recognition, spatial memory), Irwin test
Pre-pulse inhibition, gait analysis
ONCOLOGYModels: Subcutaneous human xenograft models
Read-outs Survival, clinical signs, body weight
Tumor volume, T/C
As part of Evotec’s integrated drug discovery platform, the in vivo pharmacology is further supported by DMPK and histology.
100mg/kg p.o.
30mg/kg p.o.
10mg/kg p.o.
Vehicle p.o.
Efficacy of Gabapentin in a neuropathic pain model (SNL=Spinal Nerve Ligation)
50%
resp
onse
thre
shold
(g)
5
10
15
0
Time post treatment (min)
240120600post-SNLpre-SNL
*
*
*
*
45
WHY EVOTEC?As a core value in drug discovery Evotec offers a wide range of validated and routinely used in vivo pharmacology models, DMPK as well as histology services. Evotec works closely with our clients to ensure that any custom protocols are executed to their exact specifi-cations, adapting the latest procedures from the literature. Finally Evotec will provide a detailed and accurate report on your study.
PHARMACOKINETICSObtaining pharmacokinetic data is a key requirement in the evaluation of new chemical entities. Evotec offers: Various administration routes: intravenous (incl. infusion), per os, intraperitoneal, subcutaneous, intra-cerebrospinal and intra-muscular
Cassette PK screening of up to 5 compounds simultaneously
HISTOLOGY, IMMUNOHISTOCHEMISTRY AND
MORPHOMETRIC ANALYSIS The combination of in vivo pharma-cology with histology techniques offers a powerful tool to further analyse disease relevant biomarkers. Whereas histology and IHC helps to identify disease and target rele-vant changes, automated morpho-metric analysis can yield unbiased quantitative information amenable to statistical analysis, which adds significant value to the custom-ers drug discovery effort. Further-more, histopathology on critical organ systems will allow early risk assessment.
Different matrices: blood, plasma, cerebrospinal fluid, tissues, bile, urine and faeces
Data generated with the latest version of Phoenix® WinNonlin®6.3 software, analysis performed using rigorous accep tance criteria
Plas
ma
Conc
entra
tion
(nM
)
10
100
1000
intravenous
oral
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Time (h)
0 4 8 12 16 20 24
Oral bioavailability study in rats
Immunohistochemistry and morphometric analysis of male ZDF rat pancreas: Islet of Langerhans fragmentation in male ZDF rats
OFFERINGEvotec offers its HTS/HCS platform capabilities for antibody identifica-tion including assay development, screening, hit characterisation up to in vivo pharmacology.
screening. These processes bias the screening pool in favour of affinity binders with the risk missing poten-tially interesting functional antibody clones. EVOmAb addresses this problem by offering early entry into functional selection using Evotec’s high-throughput antibody expres-sion and screening capabilities. The antibody expression platform combines high throughput cloning with high parallel expression and purification strategies. This plat-form enables the full utilisation of Evotec’s established high through-put screening capabilities.
As a partner in antibody drug development, Evotec offers cell lines over-expressing a given target or target domains for primary selections using the customers own antibody libraries and platforms.
The offering includes reformatting antibody pools from phage display selections or animal immunizations into suitable screening formats. We provide optimal cell-based HTS/HCS screening formats support-ing fast development cycles. Evotec offers a turnkey solution for antibody development up to the production of mg quantities neces-sary for testing in animal models.
CAPABILITIES AND PLATFORMEvotec has established its antibody screening platform EVOmAb to incorporate functional screening early in the antibody discovery and selection process. Attractive targets such as trans-membrane proteins need to be altered in their activity in order to achieve a meaningful pharma cological effect. Common antibody discovery campaigns employ affinity-based processes to enrich manageable number of antibody clones for functional
47
AbEXPRESSHigh parallel
expression of antibodies
CELL BASED SCREENING PLATFORMS Established at Evotec in combination with target know-how and tools
GENERATE ANTIBODY POOLS against GPCR’s, Ion channels etc. by immunisation, phage display, yeast display, …
Typical output are thousands of clones (B-cells, Hybridomas, Yeast cells) expressing no or low amounts of soluble antibody
ANTIBODY GENERATION AND SELECTIONVarious platforms available either in house (mice), through collaborations or from customers
In the previous sections of this docu-ment, we have laid out a selection of the key technical capabilities and technologies which we have on offer at Evotec, and these capabilities can be accessed as stand-alone services on demand. In addition, through our extensive drug discovery know-how and experience and expert project management, we bring seamlessly integrated drug discovery capabili-ties to bear on our collaborations. We understand that each partner has different needs, internal capabilities and capacities, so through in-depth understanding of the project goals and your specific needs, we develop a coherent plan which enables you to leverage the benefits of our large, flexible, high-quality organisation as a one-stop, cost-effective solution, no
matter where the project lies on the gene-to candidate continuum.
Each collaboration has its own indi-vidual challenges so at Evotec “we start with the end in mind”, mean-ing that we consider the intended indication, frequency and route of administration, safety and efficacy demands, early development strat-egy etc as part of the product profile which in turn impacts directly on the project plan. Our scientists work with our partner’s scientists to select and execute the most promising strategy and technologies to deliver on the project goals. We also build into our processes key decision points that will guide us through the project and continually measure our progress against these. Using this
INTEGRATEDSERVICES
Molecular biology and cloning
Bioinformatics In vitro target validation In vivo target validation Target deconvolution
Assay development and screening
(u)HTS High content screening Biophysical methods Electrophysiology In silico screening technologies
Fragment-based drug discovery
Compound management
Disease biology and target class expertise Medicinal, synthetic & computational chemistry Library design, procurement and synthesis High-throughput chemistry Protein-ligand crystallography and structure-based drug design
In vitro & in vivo pharmacology In vitro ADME, rodent PK & bioanalysis Cellular selectivity analysis Cellular MoA analysis In silico ADMET
TARGET ID & VALIDATION SCREENING HIT-TO-LEAD LEAD OPTIMISATION
Craig JohnstoneSenior Vice President Drug Discovery and Innovation Efficiency Discovery Chemistry
DISEASE BIOLOGY EXPERTISE
PROVEN PROGRAMME MANAGEMENT
SECTION 13
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WHY EVOTEC? Industry-leading capabilities in integrated drug discovery World-class suite of compound screening and profiling technologies Proven ability to progress targets to pre-clinical development within 3 years
Consistent delivery and innovation for our partners Internal processes optimised to focus on quality and speed allowing for reduced cycle times and thereby accelerating our partner’s discovery efforts
Single contracting partner reduces complexity Experienced and proven senior scientists act as project leaders and provide a single point of contact to our partner organisations
Expert advice on overall project strategy Securing IP protection and supporting grant applications
approach, we provide innovative and efficient solutions that are always focused on the needs of our partners whilst minimizing waste. Further-more, by using Evotec as a single provider of integrated services, you can spend more time thinking about the science and less time manag-ing the interfaces between multiple service providers.
Every single day, Evotec scientists are striving to solve drug discovery problems for their clients. Our scien-tists have made significant contri-butions to cutting-edge science throughout their careers and are drawn from a variety of backgrounds. They have been successful in all major therapeutic areas and target classes. Their ideas, inspiration, creativity, innovation and insight-ful analyses are all key elements of Evotec’s value proposition, and are critical contributions to successful and productive integrated collabo-rations. In addition, the conduct of such science is heavily dependent on being able to carry out the practical work smoothly, quickly, and without delays, problems, and frustration. Our client’s satisfaction, and our performance, is dependent on the effective unification of slick, produc-tive, practical execution with good ideas, problem solving and creativity: we call it “Innovation Efficiency”.
As a result of this unique combina-tion of depth, breadth, knowledge and experience of drug discov-ery with operational excellence, Evotec has established a successful track record in assisting academic institutions, not-for-profit foun-dations, biotech and pharmaceuti-cal companies in developing novel therapeutics.
Powerful combination of experience and analysis to extract learning and drive next cycle
MAKE
Rapid, relevant, high-capacity efficacy and non-efficacy testing
Excellent understanding of molecular interactions, structural insight and product
properties to enable simultaneous multi-parameter optimisation
Rapid and efficient synthetic execution.
Bespoke, complex molecules and designed libraries / sparse arrays
ANALYSIS
TEST
DESIGN
CYCLE TIME
MAKE
Integrated chemistry
and biology team at Evotec worked in collabo-ration with BI scientists, various targets and ther-apeutic focus, research funding, milestones and royalties
»Best-in-class alliance work – fruitful for both
parties«
Integrated chem-istry, biology and
DMPK team at Evotec, working with UCB scien-tists across various sites on multiple targets, minimum 3 years, research funding, milestones and royalties
»Evotec is the ideal partner to provide
the resource bandwidth and drug-hunting
expertise«
Integrated five-year multi-target collab-
oration in the field of endo-metriosis, deal structure includes upfront payment plus milestones and royal-ties
»Our new collaboration with Evotec will perfectly
complement our activities in this field
of high unmet medical need«
Integrated chem-istry and biology team at Evotec,
including high-content assays and lead optimisa-tion, recently extended to 2016 (started in 2006)
»We are impressed by Evotec’s breadth of
drug discovery expertise«
TRACK RECORDSAND CLIENTS
SECTION 14
Evotec, with its broad expertise and services, its repeat business and strategic alliances, is perfectly positioned to be your drug discovery services provider of choice. We are aware of the fact that it takes much more than just the highest qual-ity services to develop new drugs, but nevertheless this is the most im portant starting point. Evotec delivers an industrialised, high-tech, and comprehensive infrastructure to our partners.
Evotec is one of the few drug discov-ery businesses that can execute a comprehensive outsourcing strategy. Evotec provides its customers with access to the Company’s best-in-class fully integrated drug discov-ery process. In significant large-scale, multi-target deals, Evotec’s customers work with our scientists to progress discovery programmes from target through to lead optimisa-tion using the Company’s integrated drug discovery platform.
Evotec has a broad client base ranging from venture capital firms to virtual biotechs to large phar-maceutical companies. We are a truly global company with clients in the United States, Europe and Japan. We have a loyal client base with many long-term agreements as well as regular repeat clients that keep coming back with project after project as Evotec delivers the drug discovery solutions and value they need to drive their discovery programs forward.
ImprintEditor: Evotec AG; Chief Editor: Michael Bayer Content: Mario Polywka, Steven HutchinsDesign: alessandridesign, Thomas Piribauer Programming: bgcc
North America
Ryan BradyVice President, Business DevelopmentVenture Capital, Foundations & Not for [email protected]
Jeff NaroianVice President, Business Development East [email protected]
John KaminsVice PresidentBusiness DevelopmentProteomics and [email protected]
Ashley Rae KarkBusiness Development Manager Cell and protein [email protected]
Japan
Masahiko OtaniVice President Business Development, [email protected]
Christophe MullerVice President, Business DevelopmentKey [email protected]
Pharmaceutical Accounts
Europe
Hermann-Josef KaiserBusiness Development ManagerCell and protein [email protected]
