29
Presentation for The Structure Based Drug Design Conference Cambridge. MA 2009
Presentation for The Structure Based Drug Design ConferenceCambridge. MA 2009
Track Record
Domainex’s contribution to client drug discovery programmes has directly resulted in
three clinical candidates.Ion-channel blockers• Based upon several Leadbuilder-derived active series, optimisation led
to selective compounds, culminating in the identification of a clinical candidate.
Kinase Inhibitors• A close analogue of a compound we made for a client is now in clinical
trials.
Anti-thrombotics• We designed and synthesised a series of novel anti-thrombotics, and a
compound from this programme is being evaluated in clinical trials.
People
• Highly experienced team of drug hunters• >90% with PhDs.• Average age 35.• Most have significant prior experience in other
companies including: Astex, AstraZeneca, BioFocus, Celltech, DeNovo, Evotec, GSK, Medivir, Millennium, Rhone-Poulenc, UCB.
Technologies
• Combinatorial Domain Hunting (CDH) : allows us to identify soluble protein constructs for screening and structural biology.
• LeadBuilder : state-of-the-art capability in virtual screening to select small, focussed, screening sets.
• Integrated Medicinal and Computational Chemistry : for rapid progression of hits to deliver candidate drugs.
– LeadBuilder was used to select a focussed screening deck.
– Screening of this deck gave several µM and sub-µM hits, for example:
• IC50 = 0.32µM, MW 307, PSA 51Å2, LogP <4.
• Hit Identification:– We prepared a comprehensive database
of ~1000 diverse sodium and potassium channel blockers reported in the literature.
– Analysed this database to derive pharmacophores and counter-pharmacophores.
Example 1: An ion-channel blocker currently in clinical development
Example 1: An ion-channel blocker currently in clinical development
• Hit-to-lead investigation of three distinct chemical classes to improve:– Potency.– Solubility and microsomal stability.– IP position: novel biological activity, but requirement to design
away from unrelated patents.
• Resource: 3 FTE x 3 months
Domainex Competitor A Competitor B Competitor C
%inhibition @1µM 97 99 99 95
Solubility µM 194 12 0 34
% Remaining HLM 84 1 ND 1
Example 1: An ion-channel blocker currently in clinical development
• Lead compound had electrophys. IC5060nM and an acceptable physicochemical and PK profile.– But no selectivity vs closely related
ion-channels.• Comparative 3D models of the target
channel and non-targets were built.
• Lead optimisation led to selective compounds, culminating in theidentification of a Clinical Candidate.– Currently in Phase 1 Trials.
• Resource: – 3.5 FTE x 15 months.
Example 2: Kinase Lead Optimisation
• Our client requested a series of focused libraries directed at akinase target.
• Domainex designed these libraries:– To explore novel chemical space around the lead scaffold.
– Using CompoundProfiler to ensure “drug-like” properties• Predicted physicochemical and ADMET profiles• Using a combination of proprietary and in-house algorithms• Based upon the Accelrys Pipeline Pilot platform
• Library chemistries were devised and optimised by Domainex chemists.
Example 2: Kinase Lead Optimisation
• Library construction:– Domainex developed routes to the key common intermediates.
• Synthesised either in-house or sub-contracted.– Prepared the libraries using parallel synthesis methods.– Compounds prepared to >95% purity using preparative LC-MS.– A total of approx. 500 compounds delivered @ >10
mg/compound.
• Results of Biological testing:– Screening of the libraries revealed a number of active areas.– A very close analogue of one of the library members designed
and made by Domainex is currently in clinical trials.
Example 3: Protease inhibitors
• The Client’s target was a protease believed to be relevant to the treatment of asthma.
• Our starting point was a series of peptidic irreversible inhibitors:– Potent, but deemed unsuitable for further development.
• We were required to prepare reversible inhibitors that would be suitable for an inhaled therapy.
NH
NH
NH
O
O
P2
P3 P1
"Warhead""Cap"
Lead Identification
Molecular modeling
Synthesis
Screening
Lead identification:• A series of reversible “warheads”capable of interacting with the catalytic residues of the protease were investigated.• 1st generation reversible inhibitors:
IC50 in range 1-10 µM.•Resource: 2 FTE x 6 months
Example 3: Protease inhibitors
• Current lead compounds:– IC50 < 10 nM.– Good solubility, and stable in the presence
of various rat and human lung cells.– Active in animal POC studies.
• Resource : 2 FTEs x 9 months.
Lead Optimisation:
• From these leads Domainex has developed potent reversible inhibitors. – Improving interactions with the specificity pockets of the protease.– Reduce proteolytic degradation by incorporating unnatural amino
acids and/or appropriate amide isosteres at key positions.
• Structure-based drug design has played a key role in guiding the medicinal chemistry.
Example 4: “Patent busting”
• Our client wanted us to rapidly generate a patentable compound based upon a competitor’s IP.
• We undertook a careful analysis of the SAR revealed in their application and the patent claims.
• We made a handful of compounds that were novel but with a minimal number of changes from the prior art.
• One of these compounds was similar in potency to the competitor product, but with an improved PK profile and has been taken into Development.
Example 5: Hit ID for a kinase target
• Our Client postulated a novel allostericautoregulatory site – no known small molecule ligand.
• There was an x-ray structure of the protein available to us.
• We used LeadBuilder to identify small molecules that might bind to the target site.
1. Four-point pharmacophore screen.2. Docking into binding pocket.
Example 5: Hit ID for a kinase target
Crystallographically observed binding of autoinhibitory loop (red)
Four‐point pharmacophore
Example 5: Hit ID for a kinase target
• We selected 436 high-priority compounds for screening.
• Our Client tested these against the target @2µM:– Gave 27 hits (6% hit rate). – From four structural classes.
• 4 compounds showed good efficacy in a follow-up cell-based screen @ 1 µM.
• Follow-up:– Compounds are patentable.– Our Client is securing funding based upon this IP.– We are designing a hit-to-lead programme around these
series.
Further examples of our success in drug discovery…
Cytotoxic Anti-cancer Agents • Our client licensed IP for novel chemistry from a university.• We Identified a subset of these compounds that had potential for
optimisation as cancer therapeutics.• Our medicinal chemistry programme has already provided leads with
cellular activity 5-10x the commercial standards.
Enzyme Inhibitors (e.g. Kinases, Proteases)• We have carried out many client programmes, including LeadBuilder for hit
finding; lead optimisation using structure-based design; and fast-follower programmes.
• We have generated compounds active in enzyme and cellular assays, leading to novel patent filings.
Metabolic Diseases• Based upon published literature and patents, we designed and synthesised
a series of novel enzyme inhibitors with pharmacokinetic and toxicity advantages over competitors’ compounds.
• A compounds from this programme is currently in pre-clinical development.
How do we achieve this success?
Medicinal Chemistry
• A team of highly-experienced medicinal chemists:– with an industrial pedigree.– a strong track record of successful drug
discovery.• Great breadth of expertise:
– Target classes, including:• Many enzyme classes, including kinases, proteases, etc.• Cell surface receptors, such as GPCRs, cytokine receptors,
growth factor receptors, integrins, etc.• Ion channels.
– Therapeutic areas, including:• Cardiovascular, CNS, oncology, inflammation, respiratory, anti-
infectives, etc.
Medicinal Chemistry
•Drives synthesis.• Integrated design by medicinal and computational chemists.
•Holistic design (potency, ADMET, IP, etc).
•“Real time” SAR.•Experimental design.
Design
•Rapid, fit for purpose.•Parallel synthesis and microwave chemistry.
•Automated LCMS purification.
•High-quality analytical support (NMR, LCMS, etc).
Synthesis
•Can be provided by DMX if a spectrophotometric biochemical method.
•Otherwise provided by Client or by another CRO.
•DMX can also run kinetic solubility and Cyp450 inhibition assays.
Assay
Success -Quality and
speedof each cycle
LeadBuilder
• A cost-effective route to high-quality drug leads:– Significantly enhanced hit rates in compound screening.– High-quality hits – amendable to rapid progression.– Time and cost saving by comparison with HTS.– “Information-rich” hit-to-lead programmes.
• Virtual screening of curated databases of commercially available compounds, commercial drugs, etc:– Selected to be “ideal” hit structures.– Good ADMET and physicochemical profiles.– “Biophillic” to enhance hit rates.
LeadBuilder
Screening Platform
ScreenBuilder•Virtual screening
StructureBuilder•X-ray structure•Homology modelling
LibraryBuilder•Virtual Compound Collection•CompoundProfiler
BiochemicalScreening
NMRScreening
LibraryBuilder filters
100
200
300
0-2-4 -3 -1
Predicted Solubility >10µM
Drug-like
Hit-like
250 350 500
2.5
3.5
5.0
Log P
MW
Hit compound: MW 325Log P 3.0
Optimised within
drug-space
Hit-like starting points
5kcal/mol
100
200
300
Elimination of weak binders using calculated binding energies
Elimination of known toxophores, predicted good absorption
Synthetic Chemistry
• We have a team of talented PhD qualified synthetic chemists:– Many years of industrial experience. – An exceptional track record of success with demanding
chemistries.
• Expertise in:– Traditional synthesis.– Parallel synthesis of chemical libraries.– Microwave chemistry.– Solid phase and peptide synthesis.– Carbohydrate chemistry.
• Proven capabilities:– Route scouting.– Library and intermediate synthesis.– Scale-up to 10’s of grams of final compound.
Chemistry Facilities
High quality laboratories: – Fully equipped with traditional equipment
for organic synthesis.– Microwave reactor with sample handler.– Radleys Carousel and Greenhouse for
parallel synthesis.– Automated preparative LC-MS.
• Evaporation by Genevac and freeze-drying. – Analytical LC-MS and HPLC.– Local same-day access to comprehensive
analytical support (i.e. 1H & multi-nuclear NMR, IR, UV, etc).
Computational Chemistry
• Protein modelling:– Homology modelling.– Docking.
• Small-molecule modelling:– Pharmacophore analysis.– Conformational analysis.– Scaffold-morphing.
• Cheminformatics:– Target assessment: “drugability”, specificity, etc.– LeadBuilder: selection of compounds for screening.– Molecular and physicochemical property profiling.– ADME-tox prediction.
PharmaProfiler
• A highly representative selection of commercial small-molecule drugs:– 320 compounds = 30% of pharmacopeia.
• Designed for optimal coverage of drug classes and therapeutic indications.
• Ready formatted: pre-solubilised in assay-ready 96-well plates.
• Useful in a variety of screening situations, including:– lead-finding.– assay validation.– repurposing of known drugs onto novel targets.
PharmaProfiler drug classification
58Other67Other Enzyme22Cytotoxic16Transporter12Kinase13Protease14PDE25
Nuclear Receptor
33Ion Channel
74GPCR
56Other22Analgesic15Gastrointestinal58Cardiovascular75Anti-infective47Immune system40Oncology58CNS
Table 2: PharmaProfilerdrugs classified by Therapeutic Area
Oral 267
Parenteral 80
Topical 19
Table 3: PharmaProfilerdrugs classified byRoute of Administration
Table 1: PharmaProfiler drugs classified by Target Class
Conclusions
• Domainex offers a range of technologies that can be tailored to deliver a package to meet specific client needs.
• High-quality drug hunting delivered by very experienced scientists.
• We focus upon efficient communication with clients - in most cases we are fully integrated into their project teams.
