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Antibiotic Dereplication Using the Antibiotic Resistance Platform

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How were new medicines discovered?

David C Swinney¹, Jason Anthony

¹Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, California 94304, USA. david.swinney@irnd3.org

Nature Reviews. Drug Discovery

|June 25, 2011

Summary

Phenotypic screening yielded more first-in-class small-molecule drugs than target-based approaches. Focusing solely on targets may hinder drug discovery productivity.

Area of Science:

Drug discovery and development
Pharmacology
Medicinal chemistry

Background:

Analyzing drug discovery strategies and molecular mechanisms of action (MMOA) for FDA-approved agents (1999-2008).
Identifying first-in-class drugs with novel MMOAs to assess the success of different preclinical strategies.
Examining the contribution of small molecules versus biologics to first-in-class drug approvals.

Approach:

Retrospective analysis of FDA-approved drugs from 1999 to 2008.
Categorization of drugs based on discovery strategy (target-based, phenotypic, etc.) and MMOA.
Comparison of the number of first-in-class drugs originating from different preclinical approaches.

Key Points:

Out of 259 approved agents, 75 were first-in-class drugs with new MMOAs (50 small molecules, 25 biologics).

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Phenotypic screening led to more first-in-class small-molecule drugs (28) than target-based approaches (17).

This occurred despite a predominant focus on target-based strategies during the study period.

Conclusions:

Phenotypic screening demonstrates significant potential for discovering first-in-class small-molecule drugs.
A strategy prioritizing molecular targets over optimal MMOA may contribute to high attrition rates in pharmaceutical R&D.
Re-evaluating drug discovery paradigms to incorporate MMOA alongside target identification is crucial for improving productivity.