Phenotypic screening is driving some of the most exciting discoveries in biology today. Rather than starting from a preconceived notion of what target must be hit, we allow the chemical biology to identify productive therapeutic approaches. However, in starting from a phenotypic screening hit we have to adjust our lead identification process, often prioritizing <i>in vivo</i> proof-of-concept and mechanism-of-action studies even before structure-activity relationships are fully understood. And because the phenotypic assay is the starting point for all other decisions on the project, the reliability and interpretation of these phenotypic assays must be carefully considered. In this talk, we reflect on the strengths and weaknesses of this approach by citing examples from our own discovery programs, from the initial characterization of assay performance to selecting the best lead molecule. In cancer, many groups, including ourselves, have used cell killing assays as primitive phenotypic screens. When we instead chose a specific marker of cellular biology to screen against, we found richer biology to target with our small molecules. Today we have both better tools to identify a protein target from a chemical probe and better genetic tools to more rapidly validate target hypotheses to facilitate this kind of approach. Plus, we tend to have better activity when we take our hits into <i>in vivo</i> models compared with traditional target-based screening leads. These are some of the reasons why the NCATS Chemical Genomics Center at NIH invests heavily in phenotypic screening and how we identify innovative solutions to medicine’s most challenging problems.

Optimization of pyrrolo[2,3-d]pyrimidines to block the metastatic transformation of tumor cells using a high content assay

251st National Meeting (2016)

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