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The Value of Phenotypic Screening to Drug Discovery February 17, 2015 Berlin David C Swinney Ins;tute for Rare and Neglected Diseases Drug Discovery www.irnd3.org Produc9vity in the Pharma industry is decreasing NME output is not keeping up with investment Scannell et al NRDD 2011 R&D: a linear engineering process Target Asses. HTS & Lead ID Lead Opt. EIH Enabl. Ph I ECS Ph II ECE Ph III CE Launch Best used for advances in class…. not first in class Ph IV First in class requires an itera9ve learn and confirm cycle Medical Need Basic research Transla;on biomarker Drug Approval Phase 3 Efficacy Development Drug discovery is an itera;ve process star;ng with an unmet medical need and an idea to address that need. Proof of concept Clinical safety Star;ng pt (assay/target) Discovery strategy Lead iden'fica'on Discovery Pharmacological mechanism Lead op'miza'on Drug Candidates Value of phenotypic screening to drug discovery account for incomplete mechanis9c knowledge Outline Part 1 How medicines work. Part 2 How medicines were discovered. Part 3 Value of a PDD & TDD marriage. Part 1. How do medicines work? Drug ac9on begins with binding ‘Corpora non agunte nisi fixata’ A substance will not work unless it is bound -‐Paul Ehrlich, 1913 Ploeger BA, van der Graaf PH, Danhof M. Drug Metab Pharmacokinet. 2009;24:3-15. What is Molecular Mechanism of Ac9on? • MMOA: biochemical mechanism through which the structural interac;ons between the drug and its target result in a func;onal response. – Includes binding kine9c and conforma9onal changes that specifically provide a therapeu;cally useful response. • Differen;ated from Mechanism of Ac;on – systems defini;on of how a drug works – An;-‐inflammatory – An;-‐histamine – An;-‐viral Reversible binding kine9cs differen9ates aspirin from ibuprofen • Aspirin has an;-‐platelet ac;vity whereas NSAIDs do not. – Effec;ve for preven;on of atherothrombo;c disease • Both bind to the ac;ve site of cyclooxygenase 1 and 2 – Aspirin irreversible inac;va;on via acetyla;on of Ser530 – Ibuprofen and other NSAIDS are reversible • Irreversible ac;on of aspirin in platelets leads to long las;ng an;-‐ thrombo;c effects – Platelets do not have the capacity to resynthesize new protein Substrate –arachidonic acid aspirin ibuprofen Ligand specific conforma9onal changes differen9ate estrogen receptor modulators Ligand induced conforma;onal changes recruit coac;vators and corepressors in a context specific manner. Differen;ated therapeu;c use depends on unique ligand induced conforma;ons. Estradiol agonist -‐postmenopausal hormone deficiency Tamoxifen SERM (selec;ve estrogen receptor modulator) -‐breast cancer Raloxifen SERM -‐osteoporosis ER ligand binding domain Brzozowski, AM et al Nature 389, 753 (1997). 10 • Communica9on of informa9on as an analogy of MMOA – Proximity is rarely sufficient for effec;ve sharing of specific informa;on – MMOA is a language to communicate specific informa9on. The op9mal MMOA depends on the poten9al for mechanism-‐based toxicity Mechanism-‐based toxicity No Mechanism based toxicity • hit target as hard as possible • results in lower concentra;ons of drug • increase therapeu;c index – – – – – – • Molecular mechanism can provide opportunity to differen;ate efficacy from mechanism-‐based toxicity. full agonist irreversible inhibitors noncompe;;ve inhibitors insurmountable antagonists slow dissocia;on PAMs(posi;ve allosteric modulators) par;al agonists rapidly reversible inhibitors uncompe;;ve func;onally selec;ve receptor modulators – use dependent channel blockers – – – – 12 Swinney, NRDD, 3, 801, 2004 Swinney ARMC, 46, 301, 2011 PART 2 How medicines were discovered. Defini9ons-‐ • ’phenotypic screening’ -‐ any screening in which the molecular mechanism of ac;on (MMOA) that provides a tolerable therapeu;c index is not assumed. – In this context the phenotypic screening is a synonym for empirical screening. – Using this defini;on phenotypic screening includes all screening that is not target-‐based. How were new medicines discovered? The majority of small molecule -‐first in class medicines were discovered with phenotypic strategies (28 to 17) -‐followers were discovered with target-‐based strategies (83 to 30). Conclude the value of phenotypic assays is to discover new MMOAs which are difficult to a prior predict Swinney & Anthony NRDD, 10, 507, 2011 First in class medicines discovered with phenotypic screening 28 discovered by phenotypic screening Eze;mibe-‐ predecessors discovered in animal models Linozolid-‐ predecessors discovered in bacteria Cinacalcet predecessors discovered using a library of phenylalkylaminesin a bovine parathyroid cells Vorinostat: the effect of DMSO on cells due to inhibi;on of HDACs Varenicline mechanism driven approach to reduce toxicity by looking for par;al agonists Zicono;de derived from sea snail toxin First in class medicines discovered with target-‐based screening 17 discovered by target-‐based screening Maraviroc-‐ CCR5 target iden;fied from individuals with natural muta;ons Raltegravir HIV integrase inhibitor iden;fied in strand transfer assay Phenotypic screening was essen9al for many of the discoveries Mechanis9c paradox • MMOA defines medicines u;lity by – bridging between molecular interac;ons and physiology. • MMOA is difficult to a priori predict. • Hence the need for empirical phenotypic assays Iden9fica9on MMOA “pharmacological hot spot” is required for engineering approach Unmet medical need advance in class phenotypic assay Molecular, target-‐based strategy that translates to human disease chemistry focused biology focused iden9fy target, MMOA and networks of first-‐in-‐class Screen with limited mechanis9c assump9ons-‐ first in class ‘pharmacological hot spot’ Swinney, CPT 93, 299 2013 First in class approvals by US FDA 28 from PDD and 17 from TDD 1999 to 2008 Swinney & Anthony NRDD 2011 78 were from TDD and only 8 from PDD 1999 to 2013 Eder et al NRDD 2014 The discovery of first-‐in-‐class drugs: origins and evolu9on Eder, Sedrani & Weismann NRDD 13, 577, 2014 • phenotypic screening-‐ tes;ng of a large number of compounds in a systems-‐ based approach using a target-‐agnos;c assay that monitors phenotypic change. – assumes that no mechanis;c informa;on is available. • “chemocentric” was used to categorize systems-‐based approaches in which an ac;ve component had been iden;fied previously such as isola;on of aspirin from willow bark. Conclusions Eder et al • The best is yet to come if we con;nue to follow the target-‐ based approach • New technologies of HTS and genomics are only now star;ng to have a major impact • In the absence of these innova;ons the industry would run out of chemotypes as star;ng points PART 3 Value to a PDD & TDD marriage TDD -‐ most effec;ve when mechanis;c knowledge is complete PDD – Does not require complete mechanis;c knowledge Why is there such strong support for TDD? • when it works (when the target/MMOA are validated) it provides a ra;onal approach, analogous to engineering. • aligns with the poten;al for gene9cs to inform the cause of disease and provide biomarkers. • enables bejer selec;on of pa9ents for clinical trials and increases the probability of success • use structure based design to a specific target allows op9miza9on of efficacy and drug like proper;es in a ra;onal way. • used by clinical pharmacology to set doses related to target occupancy in order to maximize the therapeu;c index. • provides a metrics to communicate how the drug works to the stakeholders across the value chain, from basic researchers to chemist to developers to funders. Challenges to TDD 1. iden;fica;on and valida;on of a target. 2. Does not account for MMOA 3. Ac;ves against a target may not work in phenotypic assays What does PDD bring to the table? • Physiological relevant assays • Fewer mechanis;c assump;ons • Early safety evalua;on • Ac;ves work in phenotypic assays PDD challenges • • • • • • Phenotypic assays that are predic;ve of human disease Iden;fica;on of validated phenotypic biomarkers Unknown mechanisms of ac;on Not enabled by structure based chemical op;miza;on Challenges to select correct pa;ents for clinical trials Dose sekng for clinical trials strengths of PDD and TDD compliment their respec9ve weaknesses. WEAKNESS STRENGTHS TDD Knowledge based PDD Empirical -‐structure based design -‐PK/PD predic9ons -‐Pa9ent selec9on -‐System-‐based -‐Iden9fica9on of MMOA -‐Early safety evalua9on -‐Most available knowledge is incomplete -‐Not systems based -‐Target selec;on -‐Iden;fica;on of MMOA Difficult to use empirical findings with -‐Structure based design -‐PK/PD predic;ons -‐Pa;ent selec;on Using both PDD and TDD to address the mechanis9c paradox • TDD approaches relies on accurate understanding of the mechanism that provides a useful medicine • PDD can iden;fy chemicals and their respec;ve mechanisms (chemical biology), however the exact MMOA is difficult to iden;fy • The big ques;on for both TDD and PDD is how to move forward effec;vely with incomplete knowledge of the mechanis;c details? • The value of an integrated thinking is to use empirical/phenotypic approaches to address areas of incomplete knowledge Phenotypic screening in cancer drug discovery-‐past, present and future-‐ Moffat, Rudolph & Bailey NRDD, 13, 2014 • • • phenotypic screening iden;fies chemical en;;es that have desirable biological (phenotypic) effects on cells or organisms without having prior knowledge of their biological ac;vity or mode of ac;on against a specific molecular target(s). in prac;ce many projects are not target agnos;c; and conversely many target-‐ based discoveries rely heavily on phenotypic assays. They proposed that mechanis;cally informed phenotypic drug discovery (MIPDD) provides a basis for opportuni;es to bejer iden;fy the causal rela;onships between target inhibi;on and phenotypic effects Example: phenotypic screening known cancer drugs Axi;nib effec;vely inhibits BCR-‐ABL1(T315I) with a dis;nct binding conforma;on. Pemovska et al. Nature 2015. • TDD • PDD – Phenotypic screen – Primary cells CML & ALL pa;ents – 252 oncology compounds Axi;nib-‐ ABL1(T315I) A-‐loop in the DGF-‐in conforma;on – Binding mechanism confirmed by x-‐ray – Biochemical mechanism confirmed in cells – Provide ra;onal for tes;ng clinical u;lity in specific pa;ents Phenotypic screening accounts for incomplete mechanis9c knowledge Approved medicine Medical Need registration Development Phase 1 Clinical safety Understanding of disease empirical readouts Transla9onal biomarkers Phase 3 Efficacy Phase 2 Proof of concept Phenotypic assays Discovery strategy Itera;ons at each stage Phenotypic assays Translational biomarkers Lead identification MMOA Lead optimization Discovery Phenotypic assays Drug Candidates Empirically evaluate safety Swinney Front Pharmacol 2014 Take home messages • Empirical/phenotypic screening is valuable when mechanis9c knowledge is incomplete • The respec9ve strengths and weakness of phenotypic screening and target based screening are complimentary. • We need to wed the two approaches to provide a new genera9on of successful drug discovery
