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

Author

Listed:
  • Jayme L. Dahlin

    (National Institutes of Health
    Broad Institute)

  • 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)

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.

Suggested Citation

  • 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, 2023. "Reference compounds for characterizing cellular injury in high-content cellular morphology assays," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36829-x
    DOI: 10.1038/s41467-023-36829-x
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    References listed on IDEAS

    as
    1. Jayme L. Dahlin & Kathryn M. Nelson & Jessica M. Strasser & Dalia Barsyte-Lovejoy & Magdalena M. Szewczyk & Shawna Organ & Matthew Cuellar & Gurpreet Singh & Jonathan H. Shrimp & Nghi Nguyen & Jordan , 2017. "Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    2. Laura MacPherson & Juliana Anokye & Miriam M. Yeung & Enid Y. N. Lam & Yih-Chih Chan & Chen-Fang Weng & Paul Yeh & Kathy Knezevic & Miriam S. Butler & Annabelle Hoegl & Kah-Lok Chan & Marian L. Burr &, 2020. "HBO1 is required for the maintenance of leukaemia stem cells," Nature, Nature, vol. 577(7789), pages 266-270, January.
    3. Jonathan B. Baell & David J. Leaver & Stefan J. Hermans & Gemma L. Kelly & Margs S. Brennan & Natalie L. Downer & Nghi Nguyen & Johannes Wichmann & Helen M. McRae & Yuqing Yang & Ben Cleary & H. Rache, 2018. "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth," Nature, Nature, vol. 560(7717), pages 253-257, August.
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