The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods

• Published in: Cell chemical biology Vol. 23; no. 1; pp. 3 - 9
• Main Authors: Wagner, Bridget K., Schreiber, Stuart L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 21.01.2016
• Subjects: Animals; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chondrocytes - cytology; Chondrocytes - drug effects; Computational Biology - methods; Drug Evaluation, Preclinical - methods; Fatty Acid Desaturases - metabolism; Humans; Phenotype; Riboswitch - drug effects; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Stem Cells - cytology; Stem Cells - drug effects; Transcriptome - drug effects
• ISSN: 2451-9456; 2451-9456; 2451-9448
• DOI: 10.1016/j.chembiol.2015.11.008

The enthusiasm for phenotypic screening as an approach for small-molecule discovery has increased dramatically over the last several years. The recent increase in phenotype-based discoveries is in part due to advancements in phenotypic readouts in improved disease models that recapitulate clinically relevant biology in cell culture. Of course, a major historical barrier to using phenotypic assays in chemical biology has been the challenge in determining the mechanism of action (MoA) for compounds of interest. With the combination of medically inspired phenotypic screening and the development of modern MoA methods, we can now start implementing this approach in chemical probe and drug discovery. In this Perspective, we highlight recent advances in phenotypic readouts and MoA determination by discussing several case studies in which both activities were required for understanding the chemical biology involved and, in some cases, advancing toward clinical development. •Phenotypic screening enables medically relevant small-molecule discovery•Modern mechanism-of-action methods fuel phenotypic approaches•Integrating these activities will help discover new chemistry and biology Phenotypic screening has been a powerful approach for small-molecule discovery. However, determining the mechanism of action has been a major barrier to success. Here, we discuss several case studies that take a modern approach to both aspects, and identify new probes and clinical lead candidates.