A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases.
A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases.
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DOI：
10.1021/acschembio.5b00839
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发表时间：
2016-03-18
影响因子：
4
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Eram MS;Shen Y;Szewczyk M;Wu H;Senisterra G;Li F;Butler KV;Kaniskan HÜ;Speed BA;Dela Seña C;Dong A;Zeng H;Schapira M;Brown PJ;Arrowsmith CH;Barsyte-Lovejoy D;Liu J;Vedadi M;Jin J
蛋白质精氨酸甲基转移酶（PRMTs）在许多生物过程中起着至关重要的作用。PRMT的过表达与包括癌症在内的多种人类疾病有关。因此，PRMT的选择性小分子抑制剂已被学术界和制药工业作为测试生物学和治疗假设的化学工具。PRMT分为三类：催化精氨酸残基的单-和不对称二甲基化的I型PRMT，催化精氨酸残基的单-和对称二甲基化的II型PRMT，和仅催化精氨酸残基的单甲基化的III型PRMT。在这里，我们报告了一个有效的，选择性和细胞活性的抑制剂的人I型PRMTs，MS 023的发现，和这种抑制剂的生化，生物物理和细胞分析电池的表征。MS 023对I型PRMT（包括PRMT 1、3、4、6和8）显示出高效力，但对II型和III型PRMT、蛋白质赖氨酸甲基转移酶和DNA甲基转移酶完全无活性。与MS 023复合的PRMT 6的晶体结构揭示MS 023结合底物结合位点。MS 023有效降低组蛋白精氨酸不对称二甲基化的细胞水平。它还降低了精氨酸不对称二甲基化的总体水平，同时增加了细胞中精氨酸单甲基化和对称二甲基化的水平。我们还开发了MS 094，一种在生化和细胞测定中无活性的MS 023的类似物，作为化学生物学研究的阴性对照。MS 023和MS 094是研究I型PRMT在健康和疾病中作用的有用化学工具。
Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, 3, 4, 6 and 8, but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease.