biostudies-literatureWu FBreast Cancer Research FoundationU.S. Department of DefenseSusan G. Komen for the CureNational Cancer InstituteNCI NIH HHSCancer Prevention and Research Institute of Texas4716-4731https://www.ebi.ac.uk/biostudies/studies/S-EPMC7340344biostudies-literatureUnknown63(9)Histone acetyltransferase (HAT) p300 and its paralog CBP acetylate histone lysine side chains and play critical roles in regulating gene transcription. The HAT domain of p300/CBP is a potential drug target for cancer. Through compound screening and medicinal chemistry, novel inhibitors of p300/CBP HAT with their IC₅₀ values as low as 620 nM were discovered. The most potent inhibitor is competitive against histone substrates and exhibits a high selectivity for p300/CBP. It inhibited cellular acetylation and had strong activity with EC₅₀ of 1-3 μM against proliferation of several tumor cell lines. Gene expression profiling in estrogen receptor (ER)-positive breast cancer MCF-7 cells showed that inhibitor treatment recapitulated siRNA-mediated p300 knockdown, inhibited ER-mediated gene transcription, and suppressed expression of numerous cancer-related gene signatures. These results demonstrate that the inhibitor is not only a useful probe for biological studies of p300/CBP HAT but also a pharmacological lead for further drug development targeting cancer.Journal of medicinal chemistryDiscovery, Structure-Activity Relationship, and Biological Activity of Histone-Competitive Inhibitors of Histone Acetyltransferases P300/CBP.PMC734034417-143U54 CA233223PG12221410P50 CA186784P50CA58183RP180177RP15012918-14516-142P50 CA058183P30 CA125123W81XWH-14-1-0326Hua YNie SWu JDavis CMCoarfa CFu XLin YLKaochar SWu FYao YEhli EASchiff RMitsiades NRobertson MWu XSong YfalseDiscovery, Structure-Activity Relationship, and Biological Activity of Histone-Competitive Inhibitors of Histone Acetyltransferases P300/CBP.Histone acetyltransferase (HAT) p300 and its paralog CBP acetylate histone lysine side chains and play critical roles in regulating gene transcription. The HAT domain of p300/CBP is a potential drug target for cancer. Through compound screening and medicinal chemistry, novel inhibitors of p300/CBP HAT with their IC₅₀ values as low as 620 nM were discovered. The most potent inhibitor is competitive against histone substrates and exhibits a high selectivity for p300/CBP. It inhibited cellular acetylation and had strong activity with EC₅₀ of 1-3 μM against proliferation of several tumor cell lines. Gene expression profiling in estrogen receptor (ER)-positive breast cancer MCF-7 cells showed that inhibitor treatment recapitulated siRNA-mediated p300 knockdown, inhibited ER-mediated gene transcription, and suppressed expression of numerous cancer-related gene signatures. These results demonstrate that the inhibitor is not only a useful probe for biological studies of p300/CBP HAT but also a pharmacological lead for further drug development targeting cancer.2020-01-01T00:00:00Z2020 May2026-05-02T14:39:07.649Z2026-04-07T18:07:17.427ZS-EPMC73403443231492410.1021/acs.jmedchem.9b02164