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Nat Commun. 2017 Nov 15;8(1):1527. doi: 10.1038/s41467-017-01657-3.

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

Author information

1
Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
2
Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, 55414, USA.
3
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada, M5G 1L7.
4
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
5
Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
6
School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, China.
7
Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, 55414, USA. mwalters@umn.edu.

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.

PMID:
29142305
PMCID:
PMC5688144
DOI:
10.1038/s41467-017-01657-3
[Indexed for MEDLINE]
Free PMC Article

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