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Journal Article

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

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

Mohammad H Rohban
Ashley M Fuller
Ceryl Tan
Jonathan T Goldstein
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
TS Karin Eisinger-Mathason
Anne E Carpenter
Journal Name
Cell Systems
Publication Date
September 21, 2022