title: Phenotypic screening in cancer drug discovery - past, present and future.
abstract: 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.
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Moffat
authors.affiliation: Department of Discovery Chemistry, Genentech, South San Francisco, California 94080, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.affiliation: IOTA Pharmaceuticals, St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bailey
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D055808:Drug Discovery / Q000266:history / Q000379:methods / Q000639:trends; D004354:Drug Screening Assays, Antitumor / Q000266:history / Q000379:methods* / Q000639:trends; D005544:Forecasting; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents