Reference compounds for characterizing cellular injury in high-content cellular morphology assays.

Autor: Dahlin JL; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. jaymedahlin@gmail.com.; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA. jaymedahlin@gmail.com., Hua BK; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA., Zucconi BE; Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA., Nelson SD Jr; Stanley Center, Broad Institute, Cambridge, MA, USA., Singh S; Imaging Platform, Broad Institute, Cambridge, MA, USA., Carpenter AE; Imaging Platform, Broad Institute, Cambridge, MA, USA., Shrimp JH; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Lima-Fernandes E; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Wawer MJ; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA., Chung LPW; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA., Agrawal A; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA., O'Reilly M; Pattern, Broad Institute, Cambridge, MA, USA., Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Szewczyk M; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Li F; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Lak P; Department of Pharmaceutical Chemistry and Quantitative Biology Institute, University of California San Francisco, San Francisco, CA, USA., Cuellar M; Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, USA., Cole PA; Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA., Meier JL; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Thomas T; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Baell JB; Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Brown PJ; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Walters MA; Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, USA., Clemons PA; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA., Schreiber SL; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA., Wagner BK; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA. bwagner@broadinstitute.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Mar 13; Vol. 14 (1), pp. 1364. Date of Electronic Publication: 2023 Mar 13.
DOI: 10.1038/s41467-023-36829-x
Abstrakt: Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. Here we generate cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds that cause cellular damage produces bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.
(© 2023. The Author(s).)
Databáze: MEDLINE
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