The Contribution of Mechanistic Understanding to Phenotypic Screening for First-in-Class Medicines

The level of mechanistic understanding required for drug discovery is a central feature of most strategies. However, an understanding of mechanism is not required for regulatory approval. This paradox is particularly relevant to the role of phenotypic assays in drug discovery. A recent analysis revealed that phenotypic drug discovery strategies were more successful for first-in-class medicines, whereas target-based molecular strategies were more successful for followers (Nat. Rev. Drug Discov. 2011, 10, 507–519). The rationale for the success of phenotypic screening was the unbiased identification of the molecular mechanism of action. In this follow-up analysis, the format and mechanistic information used to establish the phenotypic assays that led to the first-in-class small-molecule new molecular entities approved by the U.S. Food and Drug Administration between 1999 and 2008 were analyzed and compared with those approved in 2012. Not surprisingly, some level of mechanistic understanding was used to select the assay formats and chemicals screened. It is concluded that mechanism takes on different connotations depending on context and perspective and that a target need not always be the exclusive definition of mechanism.