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

Nature Reviews Drug Discovery volume 13, pages 588–602 (2014)Cite this article

Subjects

Key Points

  • Drug discovery approaches for cancer, as for other therapeutic areas, have typically been divided into two classes: target-based drug discovery (TDD) and phenotypic drug discovery (PDD). Cancer drug discovery poses substantial challenges for both targeted and 'classical' phenotypic drug discovery owing to the number, diversity and plasticity of molecular mechanisms and phenotypes underlying tumour initiation and growth.

  • Discovery origins for all 48 small-molecule cancer drugs approved by the US Food and Drug Administration between 1999 and 2013, and for agents in Phase II and II clinical trials at the end of 2013, were analysed and classified.

  • Although a significant number of approved and investigational cancer drugs could be easily classified as targeted, the majority of which (21 out of 29) are kinase inhibitors, we concluded that very few drugs (four out of 48) were discovered entirely by 'classical' PDD. The remainder were discovered by, or developed from chemical lead matter discovered by a combination of phenotypic and target-based assays.

  • Drug discovery using cytoxicity assays and cancer cell lines, although yielding many of the current standard-of-care chemotherapies, is unlikely to result in further drugs with novel mechanisms of action.

  • Knowledge of the molecular pathways and targets required for specific disease-associated phenotypes, along with the ability to use more disease-relevant cell models, improves the probability of discovering drugs with novel mechanisms of action and clinical efficacy in molecularly defined patient populations.

  • We introduce the concept of 'mechanism-informed phenotypic drug discovery' (MIPDD) to include phenotypic assays for specific molecular pathways and targets. Determining the causal relationships between target inhibition and phenotypic effects may well open up new and unexpected avenues of cancer biology. Such an approach presents the best means of discovering drugs that have both an optimal molecular mechanism of action and a diagnostic hypothesis to enable patient selection leading to clinical responses.

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.

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Figure 1: Origins of new small-molecule cancer drugs approved by the FDA between 1999 and 2013.
Figure 2: Origins of new chemical entities in clinical trials for cancer.
Figure 3: Origins of phenotypically discovered cancer drugs currently in Phase III and Phase II trials.
Figure 4: A comparison between target-based drug discovery and phenotypic drug discovery, showing the linkage with mechanism-informed phenotypic drug discovery.

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Acknowledgements

The authors thank R. Blake, J. Lee, S. Malek, M. Prunotti and D. Swinney for stimulating discussions, and D. Lowe, B. Roth and the anonymous internal and external reviewers for their extremely constructive comments and suggestions.

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  1. Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, 94080, California, USA

    John G. Moffat

  2. Department of Discovery Chemistry, Genentech, South San Francisco, 94080, California, USA

    Joachim Rudolph

  3. IOTA Pharmaceuticals, St Johns Innovation Centre, Cowley Road, Cambridge, CB4 0WS, UK

    David Bailey

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Correspondence to John G. Moffat.

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J.G.M. and J.R. own stock in Hoffman-La Roche.

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Moffat, J., Rudolph, J. & Bailey, D. Phenotypic screening in cancer drug discovery — past, present and future. Nat Rev Drug Discov 13, 588–602 (2014). https://doi.org/10.1038/nrd4366

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