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Discovery of CECR2 Bromodomain Inhibitors with High Selectivities over BPTF Bromodomain

文献类型：期刊论文

作者Lu, Haibo6,7; Zu, Shijia5,6; Duan, Zhe4; Feng, Yueyao8; Wang, Jie8; Ma, Jingyi3,5; Li, Qi6; Chen, Dongying3,5; Li, Bo6; Chen, Kaixian5,6,7
刊名CHINESE JOURNAL OF CHEMISTRY
出版日期2022-06-21
页码2072-2080
关键词CECR2 bromodomain BPTF bromodomain Inhibitors Structure-activity relationships chemical probe
ISSN号1001-604X
DOI10.1002/cjoc.202200208
通讯作者Lin, Jin(linjinscu@fjmu.edu.cn)
英文摘要Comprehensive Summary Cat's eye syndrome chromosome candidate 2 bromodomain (CECR2 BRD) and Bromodomain PHD transcription factor bromodomain (BPTF BRD) are the same subfamily proteins, both of which are highly conserved in sequence and binding pockets. Challenges remain in the development of small molecules to inhibit one of the two bromodomains (BRDs), in view of each subtype may possess unique physiological and pathological functions. There is still a lack of effective selective inhibitors of CECR2 BRD, which makes it difficult to fully understand the pathogenesis of CECR2-BRD in diseases, especially cancers. Herein, we report our efforts to discover a series of highly selective CECR2 BRD inhibitors over BPTF BRD based on TP-248. Structure-based molecular optimization led to the discovery of DC-CEi-26, whose IC50 for CECR2 BRD was 96.7 +/- 14.9 nmol/L and selectivity was up to 590 x over BPTF BRD. DC-CEi-26 showed weak potencies for other classic BRDs in different subfamily, which may serve as a chemical probe for CECR2 BRD biological research.
WOS关键词CHROMATIN ; PROTEINS ; COMPLEX ; FORMS
资助项目Science and Technology Commission of Shanghai Municipality[Y811298033] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; scientific research innovation program Xiyuanjiang River Scholarship of the College of Life Sciences, Fujian Normal University ; State Key Laboratoryof Drug Research[SIMM2105KF-07] ; Fujian Provincial Natural Science Foundation[2021J01203] ; Natural Science Foundation of Fujian Province[2019J05073] ; Joint Funds for the Innovation of Science and Technology of Fujian Province[2018Y9071]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000813829700001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/301614]  
专题新药研究国家重点实验室
通讯作者Lin, Jin
作者单位1.Guizhou Univ Tradit Chinese Med, Guiyang 550025, Guizhou, Peoples R China
2.Fujian Med Univ, Sch Pharm, Fuzhou 350122, Fujian, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Pharmaceut Anal, 555 Zuchongzhi Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China
4.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China
5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
7.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
8.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Fuzhou 350117, Fujian, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Haibo,Zu, Shijia,Duan, Zhe,et al. Discovery of CECR2 Bromodomain Inhibitors with High Selectivities over BPTF Bromodomain[J]. CHINESE JOURNAL OF CHEMISTRY,2022:2072-2080.
APA Lu, Haibo.,Zu, Shijia.,Duan, Zhe.,Feng, Yueyao.,Wang, Jie.,...&Lin, Hua.(2022).Discovery of CECR2 Bromodomain Inhibitors with High Selectivities over BPTF Bromodomain.CHINESE JOURNAL OF CHEMISTRY,2072-2080.
MLA Lu, Haibo,et al."Discovery of CECR2 Bromodomain Inhibitors with High Selectivities over BPTF Bromodomain".CHINESE JOURNAL OF CHEMISTRY (2022):2072-2080.

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来源：上海药物研究所

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