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Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy

文献类型：期刊论文

作者Zhang, Zhuqing1,2; Guo, Zuhao2,3; Xu, Xiaowei1,2; Cao, Danyan3; Yang, Hong1; Li, Yanlian3; Shi, Qiongyu1; Du, Zhiyan3; Guo, Xiaobin1; Wang, Xin3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-11-25
卷号64期号:22页码:16650-16674
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01308
通讯作者Li, Jian(lijian@gmu.edu.cn) ; Geng, Meiyu(mygeng@simm.ac.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要CARM1 is a protein arginine methyltransferase and acts as a transcriptional coactivator regulating multiple biological processes. Aberrant expression of CARM1 has been related to the progression of multiple types of cancers, and therefore CARM1 was considered as a promising drug target. In the present work, we report the structure-based discovery of a series of N-1-(3-(pyrimidin-2-yl)benzyl)ethane-1,2-diamines as potent CARM1 inhibitors, in which compound 43 displays high potency and selectivity. With the advantage of excellent tissue distribution, compound 43 demonstrated good in vivo efficacy for solid tumors. Furthermore, from the detailed immuno-oncology study with MC38 C57BL/6J xenograft model, we confirmed that this chemical probe 43 has profound effects in tumor immunity, which paves the way for future studies on the modulation of arginine post-translational modification that could be utilized in solid tumor treatment and cancer immunotherapy.
WOS关键词ARGININE METHYLTRANSFERASE 1 ; TRANSCRIPTIONAL ACTIVATION ; METHYLATION ; REGULATOR ; GENE
资助项目National Natural Science Foundation of China[21922707] ; National Natural Science Foundation of China[81773572] ; Major projects of National Natural Science Foundation of China[91853126] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Open Program of State Key Laboratory of New Drug Development[SIMM2105KF-04] ; SASIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project ; Jiangxi Double Thousand Plan[Jxsq2019101064] ; GSU Molecular Basis of Disease program
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000754726000020
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/300439]  
专题新药研究国家重点实验室
通讯作者Li, Jian; Geng, Meiyu; Huang, Xun; Xiong, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
4.Gannan Med Univ, Coll Pharmaceut Sci, Ganzhou 341000, Peoples R China
5.UCAS, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Zhuqing,Guo, Zuhao,Xu, Xiaowei,et al. Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(22):16650-16674.
APA Zhang, Zhuqing.,Guo, Zuhao.,Xu, Xiaowei.,Cao, Danyan.,Yang, Hong.,...&Xiong, Bing.(2021).Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy.JOURNAL OF MEDICINAL CHEMISTRY,64(22),16650-16674.
MLA Zhang, Zhuqing,et al."Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy".JOURNAL OF MEDICINAL CHEMISTRY 64.22(2021):16650-16674.

入库方式： OAI收割

来源：上海药物研究所

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