Virtual screening for small-molecule pathway regulators by image-profile matching

• DOI: 10.1016/j.cels.2022.08.003
• Publication Date: 2022-09-02T14:29:58Z
• Authors: Mohammad H. Rohban; Ashley M. Fuller; Ceryl Tan; Jonathan T. Golds...; Deepsing Syangtan; Amos Gutnick; Ann DeVine; Madhura P. Nijsure; Megan Rigby; Joshua R. Sacher; Steven M. Corsello; Grace B. Peppler; Marta Bogaczynska; Andrew Boghossian; Gabrielle E. Ciotti; Allison T. Hands; Aroonroj Mekareeya; Minh Doan; Jennifer P. Gale; Rik Derynck; Thomas Turbyville; Joel D. Boerckel; Shantanu Singh; Laura L. Kiessling; Thomas L. Schwarz; Xaralabos Varelas; Florence F. Wagner; Ran Kafri; T.S. Karin Eising...; Anne E. Carpenter
• Keywords: YAP1; Phenotypic screening; Phenocopy

Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions candidate small molecules are tested target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match based on information public cell image data, created using Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered expected, known small-molecule for 32% positive-control gene queries. In prospective, discovery mode, we efficiently identified new related three query genes validated them subsequent gene-relevant assays, including phenocopy pheno-oppose YAP1 overexpression kill Yap1-dependent sarcoma line. This image-profile-based could replace many labor- resource-intensive accelerate biologically therapeutically useful