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Discovery of novel benzimidazole derivatives as potent p300 bromodomain inhibitors with anti-proliferative activity in multiple cancer cells

文献类型：期刊论文

作者Chen, Zonglong4; Li, Jiayi1,2; Yang, Hong3; He, Yulong4; Shi, Qiongyu3; Chang, Qi4; Liu, Ruiqi4; Huang, Xun1,2,3; Li, Yingxia4
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2022-07-15
卷号66页码:16
关键词P300 Bromodomain inhibitors CBP30 SBDD
ISSN号0968-0896
DOI10.1016/j.bmc.2022.116784
通讯作者Liu, Ruiqi() ; Huang, Xun() ; Li, Yingxia(liyx417@fudan.edu.cn)
英文摘要Adenovirus E1A-associated 300-kD protein (p300) bromodomain, which regulates gene expression by recognizing acetylated lysine (KAc) of histone, is a promising target for the treatment of cancer. Herein, a series of potent p300 bromodomain inhibitors with novel CBP30-based scaffolds was discovered through bioisosterism and conformational restriction strategies. The most promising compound 1u showed more potent inhibitory activity (IC50 = 49 nM) against p300 bromodomain and anti-proliferative activity in various cancer cell lines compared to CBP30. Moreover, 1u suppressed the expression of c-Myc and induced G1/G0 phase arrest and apoptosis in OPM-2 cells more potently than CBP30. This study provides new lead compounds for further research on the biological functions of p300.
WOS关键词C-MYC ; BINDING-PROTEIN ; CBP/P300 ; ACETYLATION ; EXPRESSION ; HATS ; CBP
资助项目National Natural Science Foundation of China-Shandong Joint Funds[U1906212] ; National Natural Science Foundation of China[21922707] ; Major projects of National Natural Science Foundation of China[81991523] ; General Program of National Natural Science Foundation of China[82173835] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000804934100003
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/301178]  
专题新药研究国家重点实验室
通讯作者Liu, Ruiqi; Huang, Xun; Li, Yingxia
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Zonglong,Li, Jiayi,Yang, Hong,et al. Discovery of novel benzimidazole derivatives as potent p300 bromodomain inhibitors with anti-proliferative activity in multiple cancer cells[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2022,66:16.
APA Chen, Zonglong.,Li, Jiayi.,Yang, Hong.,He, Yulong.,Shi, Qiongyu.,...&Li, Yingxia.(2022).Discovery of novel benzimidazole derivatives as potent p300 bromodomain inhibitors with anti-proliferative activity in multiple cancer cells.BIOORGANIC & MEDICINAL CHEMISTRY,66,16.
MLA Chen, Zonglong,et al."Discovery of novel benzimidazole derivatives as potent p300 bromodomain inhibitors with anti-proliferative activity in multiple cancer cells".BIOORGANIC & MEDICINAL CHEMISTRY 66(2022):16.

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来源：上海药物研究所

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