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

Jayme L. Dahlin (), Bruce K. Hua, Beth E. Zucconi, Shawn D. Nelson, Shantanu Singh, Anne E. Carpenter, Jonathan H. Shrimp, Evelyne Lima-Fernandes, Mathias J. Wawer, Lawrence P. W. Chung, Ayushi Agrawal, Mary O’Reilly, Dalia Barsyte-Lovejoy, Magdalena Szewczyk, Fengling Li, Parnian Lak, Matthew Cuellar, Philip A. Cole, Jordan L. Meier, Tim Thomas, Jonathan B. Baell, Peter J. Brown, Michael A. Walters, Paul A. Clemons, Stuart L. Schreiber and Bridget K. Wagner ()
Additional contact information
Jayme L. Dahlin: National Institutes of Health
Bruce K. Hua: Broad Institute
Beth E. Zucconi: Harvard Medical School and Brigham and Women’s Hospital
Shawn D. Nelson: Broad Institute
Shantanu Singh: Broad Institute
Anne E. Carpenter: Broad Institute
Jonathan H. Shrimp: National Institutes of Health
Evelyne Lima-Fernandes: University of Toronto
Mathias J. Wawer: Broad Institute
Lawrence P. W. Chung: Broad Institute
Ayushi Agrawal: Broad Institute
Mary O’Reilly: Pattern, Broad Institute
Dalia Barsyte-Lovejoy: University of Toronto
Magdalena Szewczyk: University of Toronto
Fengling Li: University of Toronto
Parnian Lak: University of California San Francisco
Matthew Cuellar: University of Minnesota
Philip A. Cole: Harvard Medical School and Brigham and Women’s Hospital
Jordan L. Meier: National Institutes of Health
Tim Thomas: University of Melbourne
Jonathan B. Baell: Monash University
Peter J. Brown: University of Toronto
Michael A. Walters: University of Minnesota
Paul A. Clemons: Broad Institute
Stuart L. Schreiber: Broad Institute
Bridget K. Wagner: Broad Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36829-x

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DOI: 10.1038/s41467-023-36829-x

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