Histone lysine acetylation is a widespread posttranslational modification, essential for vital functions in eukaryotic organisms. Histone lysine acetyltransferases (KATs) employ acetyl-coenzyme A as a universal acetyl donor for acetylation of lysine residues in histone and non-histone proteins. Despite the biomedicinal importance of modulation of the KAT activity, application of the acetyl-coenzyme A cosubstrate structure for the design of potent and selective inhibitors has been underexplored. Here, we developed functionalized coenzyme A analogs as inhibitors against human histone lysine acetyltransferases GCN5, KAT8, and HAT1. In contrast to the unmodified coenzyme A, which was found to be a poor inhibitor of GCN5 and KAT8 (IC50 > 150 μM), we showed that a ketone-substituted coenzyme A was the most potent inhibitor of GCN5 and KAT8 (IC50 = 10.9 μΜ and 13.6 μΜ, respectively). Coenzyme A and an acetamide-substituted coenzyme A efficiently inhibited HAT1 (IC50 = 7.3 μΜ and IC50 = 3.9 μΜ, respectively). Our work demonstrates that human KATs can be efficiently and selectively inhibited by S-functionalized coenzyme A, the results exhibiting significant potential towards development of highly active chemical probes for biomedically important KATs.
Voukia et al. (Thu,) studied this question.