Many compounds with highly liable chemical motifs and poor physiochemical properties are published as modulators of biomolecules without sufficient validation, and are eventually made commercially available, initiating a process which inevitably leads to their propagation in the scientific literature. For example, the use of many histone acetyltransferase (HAT) inhibitors is now routine in chemical epigenetics, as evidenced by greater than 1000 citations of the original HAT inhibitor manuscripts. Many (17/22, 77%) of the reported HAT inhibitors we tested are positive by ALARM NMR, an industry-developed 1H-13C HMQC counter-screen for promiscuous screening compounds. Selectivity panels showed many of these compounds inhibited many unrelated targets in vitro. Additional biochemical and cell-based counter-screens confirmed that most of these reported HAT inhibitors are either thiol-reactive or chemical aggregators, compound attributes which can significantly confound assay readout interpretation. These data demonstrate the utility of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many highly-touted, but insufficiently validated, chemical probes or lead compounds employed in chemical epigenetics and chemical biology.

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

253rd National Meeting (2017)

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