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Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer

文献类型：期刊论文

作者Ding, Hong2,3; Pei, Yuan3,6; Li, Yuanqing3,6; Xu, Wen7; Mei, Lianghe8; Hou, Zeng3,4,6; Guang, Yiman3,6; Cao, Liyuan1,3; Li, Peizhuo8; Cao, Haijing5
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2021-12-15
卷号52页码:12
ISSN号0968-0896
关键词Epigenetics Histone acetyltransferase P300/CBP Ovarian cancer
DOI10.1016/j.bmc.2021.116512
通讯作者Zhang, Ting(zhangting@sippr.org.cn) ; Li, Zhiyu(zhiyuli@cpu.edu.cn) ; Yang, Yaxi(yangyaxi@simm.ac.cn)
英文摘要Histone acetylation is one of the most essential parts of epigenetic modification, mediating a variety of complex biological functions. In these procedure, p300/CBP could catalyze the acetylation of lysine 27 on histone 3 (H3K27ac), and had been reported to mediate tumorigenesis and development in a variety of tumors by enhancing chromatin transcription activity. Ovarian cancer, as an extremely malignant tumor, has also been observed to undergo abnormal acetylation of histones. However, whether the treatment of ovarian cancer could be achieved by inhibiting the acetylation activity of p300/CBP on H3K27 has not been well investigated. In this article, we modified the structure of p300/CBP HAT domain inhibitor A-485 and obtained a highly active small molecule known as 13f, which has an IC50 value of 0.49 nM for inhibiting the in vitro enzyme activity of p300, as well as the anti-proliferation IC50 value on ovarian cancer cell line OVCAR-3 was 153 nM. In addition, 13f had strong acetylase family selectivity, good metabolic stability and promising in vivo anti-tumor activity in OVCAR-3 xenograft model. The discovery of 13f revealed a more active chemical entity of the HATs domain of p300/CBP and provided a novel idea for the application of epigenetic inhibitors in the treatment of ovarian cancer.
WOS关键词HISTONE ACETYLTRANSFERASE ; ACETYLATION ; CHROMATIN ; PROTEIN ; ENHANCERS ; LANGUAGE ; THERAPY
资助项目National Natural Science Foundation of China[81773568] ; National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[91753207] ; Youth innovation promotion association[2017333] ; Ministry of Science and Technology of China (National Key R&D Program of China)[2017YFB0202600] ; Personalized Medicines Molecular Signature-based Drug Discovery and Development (Strategic Priority Research Program of the Chinese Academy of Sciences)[XDA12020368]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号WOS:000774401200009
源URL[http://119.78.100.183/handle/2S10ELR8/299943]  
专题新药研究国家重点实验室
通讯作者Zhang, Ting; Li, Zhiyu; Yang, Yaxi
作者单位1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Fudan Univ, Shanghai Inst Planned Parenthood Res, Shanghai 200032, Peoples R China
6.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
7.Fudan Univ, Hosp & Inst Obstet & Gynecol, Shanghai 200011, Peoples R China
8.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Ding, Hong,Pei, Yuan,Li, Yuanqing,et al. Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2021,52:12.
APA Ding, Hong.,Pei, Yuan.,Li, Yuanqing.,Xu, Wen.,Mei, Lianghe.,...&Yang, Yaxi.(2021).Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer.BIOORGANIC & MEDICINAL CHEMISTRY,52,12.
MLA Ding, Hong,et al."Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer".BIOORGANIC & MEDICINAL CHEMISTRY 52(2021):12.

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来源：上海药物研究所

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