title: The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods.
abstract: 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.
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA. Electronic address: bwagner@broadinstitute.org.
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D044943:Fatty Acid Desaturases / Q000378:metabolism; D006801:Humans; D010641:Phenotype; D058928:Riboswitch / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects
chemical_list: D058928:Riboswitch; D054852:Small Molecule Libraries; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human