Integrating phenotypic small-molecule profiling and human genetics: the next phase in drug discovery

• Drug and target discovery will benefit from cell line genomic characterization.
• Quality cell models and selective small molecules are critical tools for success.
• The cancer field has used this approach, but other diseases would also benefit.

Over the past decade, tremendous progress in high-throughput small molecule-screening methods has facilitated the rapid expansion of phenotype-based data. Parallel advances in genomic characterization methods have complemented these efforts by providing a growing list of annotated cell line features. Together, these developments have paved the way for feature-based identification of novel, exploitable cellular dependencies, subsequently expanding our therapeutic toolkit in cancer and other diseases. Here, we provide an overview of the evolution of phenotypic small-molecule profiling and discuss the most significant and recent profiling and analytical efforts, their impact on the field, and their clinical ramifications. We additionally provide a perspective for future developments in phenotypic profiling efforts guided by genomic science.