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

作者全名："Nie, Shenyou; Wu, Fangrui; Wu, Jingyu; Li, Xin; Zhou, Chao; Yao, Yuan; Song, Yongcheng"

作者地址："[Nie, Shenyou; Wu, Fangrui; Wu, Jingyu; Li, Xin; Zhou, Chao; Yao, Yuan; Song, Yongcheng] Baylor Coll Med, Dept Pharmacol & Chem Biol, 1 Baylor Plaza, Houston, TX 77030 USA; [Song, Yongcheng] Baylor Coll Med, Dan L Duncan Canc Ctr, 1 Baylor Plaza, Houston, TX 77030 USA; [Nie, Shenyou] Chongqing Med Univ, Dept Nucl Med Affiliated Hosp 2, Therapeut Intervent Inst Life Sci, Ctr Novel Target, Chongqing 400016, Peoples R China"

通信作者："Song, YC (通讯作者)，Baylor Coll Med, Dept Pharmacol & Chem Biol, 1 Baylor Plaza, Houston, TX 77030 USA."

来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000806714900001

JCR分区：Q1

影响因子：6.7

年份：2022

卷号：237

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Histone acetyltransferase; p300/CBP; Small-molecule inhibitor; Cancer therapy

摘要："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 IC(50)s as low as 1.4 mu M. 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."

基金机构：Cancer Pre-vention and Research Institute of Texas [RP180177]; USAMRAA of the US Department of Defense [W81XWH-18-1-0368]; US National Institute of Health/National Cancer Institute [R01CA266057]

基金资助正文："Acknowledgement This work was supported by a grant (RP180177) from Cancer Pre-vention and Research Institute of Texas, a grant (W81XWH-18-1-0368) from USAMRAA of the US Department of Defense, and a grant (R01CA266057) from the US National Institute of Health/National Cancer Institute to Y.S."