Phenotypic screening in oncology drug discovery — Hosein Kouros-Mehr

A recent paper* summarized the history of oncology drug discovery and analyzes the contibutions of phenotypic drug discovery vs traditional target-based drug discovery. The authors analyze the development and mechanisms of all small molecule-based cancer drugs approved by the FDA over the past 15 years and those currently in clinical development.

The authors show that the majority of small molecule inhibitors for oncology originated in target-based discovery. However, a significant number of inhibitors were identified in phenotypic drug screening approaches. The authors suggest that the rate-limiting step in bringing compounds identified in phenotypic screenings into clinical development is the lack of mechanistically defined cellular models for the cancer phenotypes in question and also the reliance on traditional drug effects such as cytotoxicity and mitotic arrest, which are only a component of the hallmarks of cancer.

The authors suggest that mechanistically informed phenotypic models may better enable compounds identified in phenotypic screenings to successfully complete clinical development. These models would enable confirmation that the targeted agents have a molecular mechanism of action, which would enable PD biomarker development and development of diagnostic hypotheses and patient tailoring hypotheses.

* Moffat, et. al. (2014) Phenotypic screening in cancer drug discovery — past, present and future. Nat Rev Drug Discovery, doi:10.1038/nrd4366

Hosein Kouros-Mehr