Phenotypic and target-based screening: complementary or competing?

The screening of drug targets against compound libraries is now a mature and validated approach to identifying the chemical starting points of drugs. There are broadly two main screening types, namely phenotypic (often systems-based and target-agnostic) and target-based (using hypothesis-driven) approaches. These approaches were comprehensively analysed by Eder, Sedrani and Wiesmann in relation to the US Food and Drug Administration (FDA) approval of 113 first-in-class drugs in the US between 1999 and 2013.1 This analysis suggested that the majority of the first-in-class drugs were discovered through target-based approaches, with a minority originating from phenotypic screening.

This study contrasts with Swinney and Anthony’s analysis of the FDA approval of 259 agents between 1999 and 2008, which showed that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches.²

In order to reconcile the above apparently contradictory analyses, it is important to be aware that the therapeutic areas and types of drugs that were chosen for the studies could have biased the analyses and therefore the resulting conclusions. It is also important to acknowledge that the definitions of various screening methods have adapted over time to include, for example, the mechanism-informed phenotypic drug discovery that has been coined by Moffat, Rudolph and Bailey.³

As we move forward, the contributions of both phenotypic and target-based methodologies will be important in discovering new medicines and they should be seen as complementing rather than competing against each other.

References

1. Eder J, Sedrani R, Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nature Reviews Drug Discovery. 2014;13:577-587.
2. Swinney D, Anthony J. How were new medicines discovered? Nature Reviews Drug Discovery. 2011;10:507-519.
3. Moffat J, Rudolph J, Bailey D. Phenotypic screening in cancer drug discovery – past, present and future. Nature Reviews Drug Discovery. 2014;13:588-602.