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Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors

文献类型：期刊论文

作者Yang, Yaxi4; Zhang, Rukang2; Li, Zhaojun1; Mei, Lianghe6; Wan, Shili4; Ding, Hong2; Chen, Zhifeng2; Xing, Jing2; Feng, Huijin4; Han, Jie2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-02-13
卷号63期号:3页码:1337-1360
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b01721
通讯作者Zheng, Mingyue(myzheng@simm.ac.cm) ; Luo, Cheng(cluo@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要p300 and CREB-binding protein (CBP) are ubiquitously expressed pleiotropic lysine acetyltransferases and play a key role as transcriptional co-activators that are essential for a multitude of cellular processes. Despite great importance, there is a lack of highly selective, potent, druglike p300/CBP inhibitors. Through the artificial-intelligence-assisted drug discovery pipeline and further optimization, we reported the discovery of novel, highly selective, potent small-molecule inhibitors of p300/CBP histone acetyltransferases (HAT) with desired druglike properties, exemplified by B026. Our data demonstrated that B026, with half maximal inhibitory concentration (IC50) values of 1.8 nM to p300 and 9.5 nM to CBP enzyme inhibitory activity, is the most potent, selective p300/CBP HAT inhibitor. Moreover, B026 achieves significant and dose-dependent tumor growth inhibition in an animal model of human cancer, suggesting that B026 is a highly promising p300/CBP HAT inhibitor and warrants extensive preclinical investigation as a potential clinical development candidate.
WOS关键词SMALL-MOLECULE MODULATORS ; ACUTE MONOCYTIC LEUKEMIA ; CREB-BINDING PROTEIN ; CBP ; ACETYLATION ; HATS ; P53 ; TRANSCRIPTION ; REPRESSES ; TARGETS
资助项目National Key R&D Program of China[2018YFA0508200] ; National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[91753207] ; National Natural Science Foundation of China[81773568] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[21820102008] ; National Science and Technology Major Project[2018ZX09711002-004-012] ; National Science and Technology Major Project[2018ZX09711002-004-013] ; National Science and Technology Major Project[2018ZX09711002-006-001] ; National Science and Technology Major Project[2018ZX09711002-008-005] ; Chinese Academy of Sciences[XDA12020361] ; Science and Technology Commission of Shanghai Municipality[17QA1405000] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; K. C. Wong Education Foundation ; Youth innovation promotion association[2017333]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000514221700028
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/281284]  
专题新药研究国家重点实验室
通讯作者Zheng, Mingyue; Luo, Cheng; Zhou, Bing
作者单位1.Dezhou Univ, Sch Informat Management, Dezhou 253023, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Suzhou Inst Drug Innovat, Shanghai Inst Mat Med, Suzhou 213000, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Yaxi,Zhang, Rukang,Li, Zhaojun,et al. Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(3):1337-1360.
APA Yang, Yaxi.,Zhang, Rukang.,Li, Zhaojun.,Mei, Lianghe.,Wan, Shili.,...&Zhou, Bing.(2020).Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,63(3),1337-1360.
MLA Yang, Yaxi,et al."Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 63.3(2020):1337-1360.

入库方式： OAI收割

来源：上海药物研究所

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