Structure-activity relationship and antitumor activity of 1,4-pyrazine-containing inhibitors of histone acetyltransferases P300/CBP

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. [Display omitted] •Compound screening identified 1,4-pyrazines and their analogs as novel inhibitors of human histone acetyltransferase p300.•Structure-activity relationship studies yielded a more potent compound 29.•Enzyme kinetics and other studies support compound 29 is competitive against the substrate histone.•Compound 29 exhibited a high selectivity for histone acetyltransferase p300 and its paralog CBP.•Compound 29 inhibited cellular histone acetylation and proliferation of a panel of solid and blood cancer cells.