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

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

  • Eur J Med Chem. 2022 Jul 5;237:114407. doi: 10.1016/j.ejmech.2022.114407.
Shenyou Nie 1 Fangrui Wu 1 Jingyu Wu 1 Xin Li 1 Chao Zhou 1 Yuan Yao 1 Yongcheng Song 2
Affiliations

Affiliations

  • 1 Department of Pharmacology & Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
  • 2 Department of Pharmacology & Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. Electronic address: ysong@bcm.edu.
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.

Keywords

Cancer therapy; Histone acetyltransferase; Small-molecule inhibitor; p300/CBP.

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