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Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia

文献类型：期刊论文

作者Guo, Zuhao1; Zhang, Zhuqing2,3; Yang, Hong2; Cao, Danyan1; Xu, Xiaowei2,3; Zheng, Xineng2,3; Chen, Danqi1; Wang, Qi1,3; Li, Yanlian1; Li, Jian1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-06-13
卷号62期号:11页码:5414-5433
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b00297
通讯作者Geng, Meiyu(mygeng@simm.ac.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.
WOS关键词ANDROGEN RECEPTOR ; HISTONE H3 ; COACTIVATOR ; CARM1 ; METHYLATION ; DISCOVERY ; TRANSCRIPTION ; EXPRESSION
资助项目National Natural Science Foundation of China[91853126] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020371] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020365] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-004-002] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-004-014] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Shanghai Talent Development Founds[201663]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000471834500012
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/289534]  
专题新药研究国家重点实验室
通讯作者Geng, Meiyu; Huang, Xun; Xiong, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Zuhao,Zhang, Zhuqing,Yang, Hong,et al. Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(11):5414-5433.
APA Guo, Zuhao.,Zhang, Zhuqing.,Yang, Hong.,Cao, Danyan.,Xu, Xiaowei.,...&Xiong, Bing.(2019).Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.JOURNAL OF MEDICINAL CHEMISTRY,62(11),5414-5433.
MLA Guo, Zuhao,et al."Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia".JOURNAL OF MEDICINAL CHEMISTRY 62.11(2019):5414-5433.

入库方式： OAI收割

来源：上海药物研究所

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