biostudies-literatureVoukia FEuropean Research CouncilLundbeck Foundation477https://www.ebi.ac.uk/biostudies/studies/S-EPMC12899889biostudies-literatureUnknown31(3)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 cMolecules (Basel, Switzerland)Inhibition of Histone Lysine Acetyltransferases by Coenzyme A Analogs.PMC12899889715691R344-2020-1051Andersen SBBilgin NMecinovic JVoukia FfalseInhibition of Histone Lysine Acetyltransferases by Coenzyme A Analogs.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 c2026-01-01T00:00:00Z2026 Jan2026-07-09T13:12:22.99Z2026-07-09T13:09:13.589ZS-EPMC128998894168345310.3390/molecules31030477