Publication Date
7-5-2022
Journal
European Journal of Medicinal Chemistry
DOI
10.1016/j.ejmech.2022.114407
PMID
35512565
PMCID
PMC9165588
PubMedCentral® Posted Date
7-5-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Acetylation, Acetyltransferases, Enzyme Inhibitors, Histone Acetyltransferases, Histones, Humans, Lysine, Neoplasms, Pyrazines, Structure-Activity Relationship, Histone acetyltransferase, p300/CBP, small-molecule inhibitor, cancer therapy
Abstract
Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibitor of p300 HAT against the substrate histone. It exhibited a high selectivity for p300 and CBP, with negligible activity on other classes of HATs in human. Compound 29 inhibited cellular acetylation of several histone lysine residues and showed strong activity against proliferation of a panel of solid and blood cancer cells. These results indicate it is a novel pharmacological lead for drug development targeting these cancers as well as a useful chemical probe for biological studies of p300/CBP.
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Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Medical Sciences Commons, Medical Specialties Commons
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