Many previously reported histone acetyltransferase (HAT) inhibitors have significant assay interference and off-target liabilities in cell-free and cellular assays. Potent and specific cell-active p300/CBP (A-485) and KAT6A/B inhibitors (WM-8014 and WM-1119) were recently reported. Given the historic liabilities of this small-molecule inhibitor class, we profiled these new chemical probes for common interference mechanisms and cellular activities. These next-generation probes and their corresponding inactive analogs had clean interference profiles, including lack of gross reactivity with several biological thiols, no evidence of colloidal aggregate formation, minimal light-based interferences, and gross chemical stability in assay-like conditions. These next-generation HAT inhibitors showed cellular readouts distinct from common interference compounds in cellular histone acetylation assays, cellular health assays, and live-cell imaging. Using cell painting with U-2 OS cells, these next-generation HAT inhibitors showed morphological profiles distinct from prototypical interference compounds (aggregators, redox-active compounds, nonspecific thiol reactive compounds) and historical HAT inhibitors. These data suggest these newer HAT inhibitors show promise as useful and robust tools for chemical epigenetics.

Assay interference profiles of next-generation cell-active histone acetyltransferase inhibitors

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.