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Hit to Lead Michael Rafferty 1 Hit to Lead Michael Rafferty Hit to Lead Michael Rafferty Ph.D. Department of Medicinal Chemistry University of Kansas [email protected] 1 Background • Ph.D. Medicinal Chemistry, University of Kansas • Postdoctoral Fellowship, NIH • 25+ years experience in drug discovery with Parke-Davis, Bristol-Myers, Searle, and Pfizer • Current affiliations: Adjunct Prof., Department of Medicinal Chemistry, University of Kansas 2 Recommended readings • Alanine et al. (2003) Lead Generation- Enhancing the Success of Drug Discovery by Investing in the Hit to Lead Process, Combinatorial Chemistry and High Throughput Screening 6: 51-66 • Barelier and Krimm (2011) Ligand Specificity, Privileged Substructures and Protein Druggability from Fragment-Based Screening, Curr. Opin. Chem. Biol. 15: 469-474 • Bleicher et al. (2003) Hit and Lead Generation: Beyond High Throughput Screening, Nat. Rev. Drug Disc. 2: 369-378 • Ferenczy and Keseru (2010) Enthalpic Efficiency of Ligand Binding, J. Chem. Inf. Model. 50: 1536-1541 • Ferenczy and Keseru (2012) Thermodynamics of Fragment Binding, J. Chem. Inf. Model. 52: 1039-1045 • Gleeson et al. (2011) Probing the Links Between in vitro Potency, ADMET, and Physicochemical Parameters, Nat. Rev. Drug. Disc. 10: 197-208 • Hann (2011) Molecular Obesity, Potency, and Other Addictions in Drug Discovery, Med. Chem. Commun. 2: 349-355 • Hann and Keseru (2012) Finding the Sweet Spot: The Role of Nature and Nurture in Medicinal Chemistry, Nat. Rev. Drug Disc. 11: 355-365 •Hannet al. (2001) Molecular Complexity and its Impact on the Probability of Finding Leads for Drug Discovery, J. Chem. Inf. Comput. Sci. 41: 856-864 • Keseru and Makara (2009) The Influence of Lead Discovery Strategies on the Properties 3 of Drug Candidates, Nat. Rev. Drug Disc. 8: 203-212 The screen versions of these slides have full details of copyright and acknowledgements 1 Hit to Lead Michael Rafferty Presentation outline • What is “Hit to Lead”? ¾ Definitions ¾ Objectives • Getting from Hit… ¾ Definition of a Hit ¾ Hit sources ¾ Selecting a Hit • …to Lead ¾ Technologies and Resourcing ¾ Hit to Lead Strategies • Factors which Influence HtL Success • Case Studies 4 • Concluding Comments The drug discovery process HtL LD LO Hit Lead Series Candidate Focus on target Focus on identifying Focus on fine tuning potency and selectivity; a novel series with ADMET properties defined in vitro the desired activity to identify one properties profile profile including or more preclinical functional activity development candidates in vitro and in vivo, with refinement of physical properties • Drug Discovery “…often resembles an unpredictable journey on a chaotic surface rather than a quantitative and predictive science.” (Hann (2011), Med. Chem. Commun. 2: 349-255) Images5 reproduced with permission from Monarch Watch, University of Kansas www.monarchwatch.edu Hit to Lead evolved in the 1990’s to address a growing problem with drug candidate failures • In the “old” days— ¾ Focus only on potency; SAR advancement emphasized potency with minimal consideration of other attributes ¾ Result: compounds with poor bioavailability, high clearance, high risk off-target effects, low solubility and low dissolution properties, clinical trial failures ¾ Success rate of drug candidates from candidate nomination to market: 4-6% The modern day HtL process was developed to identify and eliminate poor quality leads right up front 6 The screen versions of these slides have full details of copyright and acknowledgements 2 Hit to Lead Michael Rafferty The Hit to Lead process • “Hit to Lead” is the first engagement of medicinal chemistry in the Drug Discovery continuum • The objective of “Hit to Lead” is to identify and advance the highest quality chemical starting points for a small molecule drug discovery program Validated Validated Lead Ta r g e t 1° Hits Hits SAR Series Literature HTS FBS Confirmation VS Calculated properties Analogue testing Measured properties Preliminary chemistry Prioritization Multidimensional SAR This process is designed to quickly and efficiently determine whether a quality lead can be found, and identify issues or limitations that will need 7 to be addressed during later stages of the Discovery Process 1: Hit validation and prioritization 8 Sources of hits For most early discovery programs, the biggest challenge is not in finding hits, but in finding a few good hits! • Literature • Natural Products/Ligands • High Throughput Screening (HTS) • Fragment Screening (FBS) • Docking and Scoring (Virtual Screening, VS) 9 The screen versions of these slides have full details of copyright and acknowledgements 3 Hit to Lead Michael Rafferty Hit selection has evolved into an extensive filtering process reliant on a great deal of information 1° Hits In silico filters (>500) Filtered list retest 2° testing Refined Confirmed HtL candidates Advances in computational (“in silico”) methods to calculate properties and rank hits have enriched hit prioritization and decision-making enormously, along with development of an array of plate-based, miniaturized screens 10 for activity and ADMET properties Readily calculated properties of hits • Molecular weight (MW) • Molecular volume and dimensions • Calculated partition coefficient (clogP) • # rotatable bonds • Total polar surface area (tPSA) • # aromatic rings • Hydrogen bond donors and acceptors • Ionization constant (pKacalc) • logD (partition coefficient at pH X) • Physical properties influence the behavior of a compound in the tissue and the effectiveness of the treatment • Properties for most marketed drugs fall within a well-defined range of values 11• Lipinski’s ‘Rule of 5’ used to define potential drug candidates In silico structural property “filters” • “Structural Alerts”- structural features which have known associations with toxicity, metabolic lability, poor physicochemical attributes • Toxicity predictors (“Derek”) • Similarity-based clustering (a hit “series” is preferred over singletons) • Historical database mining - evidence of promiscuity, off target risk; can also serve to confirm activity at the desired target for a hit that has previously been found to be active in a closely related target family member 12 The screen versions of these slides have full details of copyright and acknowledgements 4 Hit to Lead Michael Rafferty Additional testing during the hits selection process • Confirmation of structure, purity (HTS hits) ¾ DMSO solvated libraries may degrade over time ¾ Assumed concentrations may be off by 10X due to several factors • Confirmation of on-target activity; potency, kinetics ¾ Demonstration of reversible kinetics, determination of potency, specificity (“promiscuous aggregators”*) • Selectivity vs. target family members and vs. antitargets ¾ Microsomal clearance, hERG channel binding, P450 inhibition • In vitro determinations of solubility, permeability ¾ Automated plate based methods • For a select few of the most interesting candidates: in vivo clearance, oral dose exposure, plasma protein binding *Jadhav et al., Quantitative analyses of aggregation, autofluorescence, and reactivity artifacts in a screen for inhibitors of a thiol protease, J. Med. Chem. (2010) 53 (1), 37-51 and earlier papers; 13 See also Schoichet Lab website, http://shoichetlab.compbio.ucsf.edu/take-away.php Some HTS hits examples O H NH H N NH O O N N N N N H N H2N N N NH N S 2. 3. 4. 1. N COOH N Targets: 5. Me FabI O NHMe Bcr-Abl N MeO H N PTPase OMe O 8. COOH MeO N N H Me H N N CCR2b 6. OMe O NH N O COOH γ-secretase 7. H COOH 9. NPY Y5 H H H N N N N O H 5-HT2c Cl N NH N O Br N S Lp-PLA2 10. Me Me Cl 11. N 12. MTP O ORL1 O O N N NH H N S N N 14. H 14 13. Fragment screening vs. HTS • Fragment hits are generally low MW, highly efficient enthalpically driven ligands Hopkins, et al., Drug Discovery Today, 2004, 9: 430-431 15Rees et al., Nature Reviews Drug Disc. 2004 3: 660-672 The screen versions of these slides have full details of copyright and acknowledgements 5 Hit to Lead Michael Rafferty Examples of fragments identified vs. various protein targets Taken from 2009 AACR presentation (David Rees) 16Hartshorn et al., J Med Chem 2005, 48(2): 403-13 Factors which influence hit quality 1. The source of the hit ¾Natural product leads tend to be structurally complex 2. The nature of the screening library ¾Historical compound collections are a legacy of past discovery programs; poorly managed DMSO solvated libraries may show considerable degradation 3. The quality and precision of the screening method ¾Noisy or low resolution screens introduce high false positives 4. The nature of the molecular target* ¾Molecular targets designed to interact with lipoidal ligands/substrates tend to favor lipophilic hits; protein-protein interfaces favor structurally complex (high MW) ligands *Morphy (2006) J. Med. Chem. 49: 2969-2978; 17 Viethand Sutherland (2006) J. Med. Chem. 49: 3451-3453 Simple metrics for hit selection & prioritization • Lipinski “Rule of 3” for “Lead-Like” Hits ¾ MW < 300 ¾ H-bond donors ≤ 3 ¾ H-bond acceptors ≤ 6 ¾ cLogP < 3 Additional considerations: ¾ tPSA < 60 ang2 ¾ LE > 4 Lipinski (2000) J. Pharmacol. Toxicol. Methods 44: 235-249 18 Congreve et al. (2003) Drug Discovery Today 8: 876-877 The screen versions of these slides have full details of copyright and acknowledgements 6 Hit to Lead Michael Rafferty 2. Hit to Lead process and strategies 19 HtL resourcing and technologies • Hit to Lead chemistry is typically a short term (≤ 6 months) investigation of structure-activity relationships • Many Pharmas now employ dedicated
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