Nature Reviews Drug Discovery 13, 588-602 (August 2014) | doi:10.1038/nrd4366

Phenotypic screening in cancer drug discovery — past, present and future

John G. Moffat1, Joachim Rudolph2 & David Bailey3  About the authors


There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology.

Author affiliations

  1. Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080, USA.
  2. Department of Discovery Chemistry, Genentech, South San Francisco, California 94080, USA.
  3. IOTA Pharmaceuticals, St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UK.

Correspondence to: John G. Moffat1 Email:

Published online 18 July 2014

Additional data