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Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases

文献类型：期刊论文

作者Li, Xiao2,3,4; Zhang, Lun2; Xu, Jing2; Liu, Chenyu5; Zhang, Xiaojian5; Abdelmoneim, Amr Abbas2; Zhang, Qian2; Ke, Jiaqi2; Zhang, Yingnan2; Wang, Lei2
刊名JOURNAL OF CHEMICAL INFORMATION AND MODELING
出版日期2022-02-14
卷号62期号:3页码:692-702
ISSN号1549-9596
DOI10.1021/acs.jcim.1c01100
通讯作者Jin, Jia(aukaukauk@163.com) ; Ye, Fei(yefei@zstu.edu.cn)
英文摘要CARM1 (coactivator-associated arginine methyl-transferase 1), which belongs to type I PRMTs (protein arginine methyltransferases), is a potential therapeutic target for treatment of multiple cancers. In this study, we first identified several hit compounds against CARM1 by structure-based virtual screening (IC50 = 35.51 +/- 6.68 to 68.70 +/- 8.12 mu M) and then carried out chemical structural optimizations, leading to six compounds with significantly improved activities targeting CARM1 (IC50 = 18 +/- 2 to 107 +/- 6 nM). As a compound with an ethylenediamino motif, the most potent inhibitor, ZL-28-6, also exhibited potent inhibition against other type I PRMTs. Compared to the type I PRMT inhibitor from our previous work (DCPR049_12), ZL-28-6 showed increased potency against CARM1 and decreased activity against other type I PRMTs. Moreover, ZL-28-6 showed better antiproliferation activities toward a series of solid tumor cells than DCPR049_12, indicating its broad spectrum of anticancer activity. In addition, cellular thermal shift and Western blot assays validated that ZL-28-6 could target CARM1 in cells. Taken together, the inhibitor we identified could serve as a potent probe for studying CARM1's biological functions and shed light on the future design of novel CARM1 inhibitors with stronger activities and selectivities.
WOS关键词CARM1 ; METHYLATION ; INSIGHTS ; PAINS
资助项目National Natural Science Foundation of China[81803339] ; Zhejiang Provincial Top Key Discipline of Biology
WOS研究方向Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000762974500024
源URL[http://119.78.100.183/handle/2S10ELR8/299704]  
专题新药研究国家重点实验室
通讯作者Jin, Jia; Ye, Fei
作者单位1.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310000, Peoples R China
2.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Peoples R China
3.Chinese Acad Sci, Ctr Chem Biol, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai 200062, Peoples R China
6.Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Peoples R China
推荐引用方式
GB/T 7714		 Li, Xiao,Zhang, Lun,Xu, Jing,et al. Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2022,62(3):692-702.
APA Li, Xiao.,Zhang, Lun.,Xu, Jing.,Liu, Chenyu.,Zhang, Xiaojian.,...&Ye, Fei.(2022).Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases.JOURNAL OF CHEMICAL INFORMATION AND MODELING,62(3),692-702.
MLA Li, Xiao,et al."Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases".JOURNAL OF CHEMICAL INFORMATION AND MODELING 62.3(2022):692-702.

入库方式： OAI收割

来源：上海药物研究所

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