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Phenotypic screening in cancer drug discovery - past, present and future
John G Moffat1, Joachim Rudolph2, David Bailey3
1Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080, USA.
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.
Insights
Phenotypic screening contributes to oncology drug discovery, though its impact is limited by nonspecific effects and a lack of defined cellular models. Advances in technology can enhance phenotypic drug discovery for cancer.
Area of Science:
- Oncology
- Drug Discovery
- Pharmacology
Background:
- Resurgence of interest in phenotypic screening for drug discovery as an alternative to target-focused approaches.
- Oncology is a highly active therapeutic area where target-focused approaches have dominated drug discovery.
- Investigation into the role of phenotypic assays in oncology drug discovery.
Observation:
- Analysis of new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over 15 years and those in clinical development.
- Majority of drugs originated from target-based discovery.
- A significant number of drugs were identified as originating from phenotypic screening approaches.
Findings:
- Phenotypic screening's contribution to cancer drug discovery is hindered by reliance on nonspecific effects (e.g., cytotoxicity, mitotic arrest).
- A scarcity of mechanistically defined cellular models for therapeutically relevant cancer phenotypes further limits phenotypic screening.
- Technical and biological advancements are enabling mechanistically informed phenotypic models.
Implications:
- Mechanistically informed phenotypic models have the potential to significantly empower phenotypic drug discovery in oncology.
- Future drug discovery efforts can leverage these advances to overcome current limitations.
- This approach may lead to novel cancer therapeutics.
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