Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors

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 L. Meier, Cheryl H. Arrowsmith, Peter J. Brown, Jonathan B. Baell and Michael A. Walters ()
Additional contact information
Jayme L. Dahlin: Brigham and Women’s Hospital
Kathryn M. Nelson: University of Minnesota
Jessica M. Strasser: University of Minnesota
Dalia Barsyte-Lovejoy: University of Toronto
Magdalena M. Szewczyk: University of Toronto
Shawna Organ: University of Toronto
Matthew Cuellar: University of Minnesota
Gurpreet Singh: University of Minnesota
Jonathan H. Shrimp: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Nghi Nguyen: Monash Institute of Pharmaceutical Sciences, Monash University
Jordan L. Meier: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Cheryl H. Arrowsmith: University of Toronto
Peter J. Brown: University of Toronto
Jonathan B. Baell: Monash Institute of Pharmaceutical Sciences, Monash University
Michael A. Walters: University of Minnesota

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology.

Date: 2017
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DOI: 10.1038/s41467-017-01657-3

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