We analysed the discovery strategies and the molecular mechanisms of action (MMOAs) for new molecular entities and new biologics that were approved by the US Food and Drug Administration (FDA) in the 10-year period between 1999 and 2008.
Out of the total of 259 agents approved, 75 were first-in-class drugs with new MMOAs, and of these, 50 (67%) were small molecules and 25 (33%) were biologics.
These results show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from these two approaches, respectively — in an era in which the major focus was on target-based approaches.
There were 164 follower drugs, of which 83 (51%) were discovered with target-based approaches, 30 (18%) via phenotypic assays and 31 (19%) were biologics.
Many different biochemical mechanisms mediated the drug response at the target. These included: reversible, irreversible and slow binding kinetics; competitive, uncompetitive and noncompetitive interactions between physiological substrates/ligands and drugs; and inhibition, activation, agonism, partial agonism, allosteric activation and induced degradation, among other mechanisms. We conclude that an affinity-driven 'one size fits all' approach to drug discovery does not account for the diversity of MMOAs of approved drugs.
We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
We consider that technical risk — and, consequently, overall attrition in drug development — could be decreased for first-in-class drugs through the development and greater use of translational phenotypic assays and by considering diverse MMOAs when using a target-based, hypothesis-driven strategy.
Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
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We wish to acknowledge the employees of Roche (Palo Alto) who created a great environment to do drug discovery research. We specifically thank the members of the Biochemical Pharmacology Core led by A. Ford and the Virology Disease Biology Area led by N. Cammack for their support and encouragement. D.C.S. also wishes to thank the many scientists whose feedback, constructive criticism and desire to discover new medicines helped to provide the motivation for this work.
David Swinney started this work while he was an employee of Roche Palto Alto, and is currently the CEO and co-founder of the Institute for Rare and Neglected Diseases Drug Discovery.
Jason Anthony declares no competing financial interests.
Supplementary Information (Table S1)
Set of drugs analysed (XLS 81 kb)
Supplementary Information (Box S2)
Discovery of first-in-class medicines 1999-2008 (PDF 488 kb)
- New molecular entities
(NME). A medication containing an active ingredient that has not been previously approved for marketing in any form in the United States.
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Swinney, D., Anthony, J. How were new medicines discovered?. Nat Rev Drug Discov 10, 507–519 (2011). https://doi.org/10.1038/nrd3480
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