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Structure Based Drug Design


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Medicinal chemistry Capabilities

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Structure Based Drug Design

  1. 1. Presentation for The Structure Based Drug Design Conference Cambridge. MA 2009
  2. 2. 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.
  3. 3. 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.
  4. 4. 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.
  5. 5. Example 1: An ion-channel blocker currently in clinical development • 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. – 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.
  6. 6. 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. 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 • Resource: 3 FTE x 3 months
  7. 7. Example 1: An ion-channel blocker currently in clinical development • Lead compound had electrophys. IC50 60nM 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 the identification of a Clinical Candidate. – Currently in Phase 1 Trials. • Resource: – 3.5 FTE x 15 months.
  8. 8. Example 2: Kinase Lead Optimisation • Our client requested a series of focused libraries directed at a kinase 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.
  9. 9. 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.
  10. 10. 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. "Warhead" O P2 "Cap" H H Lead identification: N N N • A series of reversible “warheads” H P3 O P1 capable of interacting with the catalytic residues of the protease were investigated. Molecular modeling • 1st generation reversible inhibitors: Synthesis IC50 in range 1-10 µM. Screening •Resource: 2 FTE x 6 months Lead Identification
  11. 11. Example 3: Protease inhibitors 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. • 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.
  12. 12. 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.
  13. 13. Example 5: Hit ID for a kinase target • Our Client postulated a novel allosteric autoregulatory 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.
  14. 14. Example 5: Hit ID for a kinase target Crystallographically observed  Four‐point pharmacophore binding of autoinhibitory loop (red)
  15. 15. 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.
  16. 16. 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.
  17. 17. How do we achieve this success?
  18. 18. 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.
  19. 19. Medicinal Chemistry Design Synthesis • Drives synthesis. • Rapid, fit for purpose. • Integrated design by • Parallel synthesis and medicinal and microwave chemistry. computational • Automated LCMS chemists. Success - purification. • Holistic design Quality and • High-quality analytical (potency, ADMET, IP, speed support (NMR, LCMS, etc). of each cycle etc). • “Real time” SAR. • Experimental design. • Can be provided by DMX if a spectrophotometric biochemical method. • Otherwise provided by Client or by Assay another CRO. • DMX can also run kinetic solubility and Cyp450 inhibition assays.
  20. 20. 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.
  21. 21. LeadBuilder LibraryBuilder •Virtual Compound Collection •CompoundProfiler StructureBuilder ScreenBuilder •X-ray structure •Virtual screening •Homology modelling Screening Platform Biochemical NMR Screening Screening
  22. 22. LibraryBuilder filters Log P Hit-like starting points 5.0 Optimised Elimination of within 300 weak binders Drug-like drug-space 3.5 using Hit-like calculated 200 Hit compound: binding 2.5 MW 325 Log P 3.0 energies 100 250 350 500 MW 5kcal/mol 300 Elimination of Predicted known Solubility toxophores, 200 >10µM predicted good absorption 100 -4 -3 -2 -1 0
  23. 23. 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.
  24. 24. 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).
  25. 25. 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.
  26. 26. 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.
  27. 27. PharmaProfiler drug classification GPCR 74 Ion Channel 33 Nuclear Receptor 25 CNS 58 PDE 14 Oncology 40 Protease 13 Immune system 47 Kinase 12 Anti-infective 75 Transporter 16 Cardiovascular 58 Oral 267 Cytotoxic 22 Gastrointestinal 15 Parenteral 80 Other Enzyme 67 Analgesic 22 Other 56 Topical 19 Other 58 Table 1: Table 2: PharmaProfiler Table 3: PharmaProfiler PharmaProfiler drugs drugs classified by drugs classified by classified by Target Therapeutic Area Route of Administration Class
  28. 28. 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.