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

Author:Rohban M H, Fuller A M, Tan C, et al.?

Journal:

Cell Systems, 2022, 13(9): 724-736. e9.

Abstract:Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing ther_x005F apeutics 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 heno-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 discov ery of biologically and therapeutically useful compounds.