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Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01134
Chen Wang 1, 2, 3 , Hao Jiang 2, 3 , Jia Jin 1 , Yiqian Xie 2 , Zhifeng Chen 4 , Hao Zhang 2 , Fulin Lian 2 , Yu-Chih Liu 5 , Chenhua Zhang 5 , Hong Ding 2 , Shijie Chen 2 , Naixia Zhang 2 , Yuanyuan Zhang 2 , Hualiang Jiang 2 , Kaixian Chen 2, 4 , Fei Ye 1 , Zhiyi Yao 6 , Cheng Luo 2
Affiliation  

Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of N1-(2-((2-chlorophenyl)thio)benzyl)-N1-methylethane-1,2-diamine (28d, DCPR049_12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases. Compound 28d effectively inhibits cell proliferation in several leukemia cell lines and reduces the cellular asymmetric arginine dimethylation levels. Serving as an effective inhibitor, 28d demonstrates the mechanism of cell killing in both cell cycle arrest and apoptotic effect as well as downregulation of the pivotal mixed lineage leukemia (MLL) fusion target genes such as HOXA9 and MEIS1, which reflects the critical roles of type I PRMTs in MLL leukemia. These studies present 28d as a valuable inhibitor to investigate the role of type I PRMTs in cancer and other diseases.

中文翻译:

白血病细胞增殖的强效I型蛋白精氨酸甲基转移酶(PRMT)抑制剂的开发

蛋白质精氨酸甲基转移酶(PRMT)在多种生物过程中起着至关重要的作用,PRMT的失调与多种人类疾病(尤其是癌症)有关。因此,靶向PRMT的小分子对于学术功能研究和临床疾病治疗都具有深远的影响。在这里,我们报道了N 1-(2-(((2-氯苯基)硫基)苄基)-N 1-甲基乙烷-1,2-二胺(28d,DCPR049_12)的发现,这是一种高效的I型PRMTs抑制剂,具有对一组其他甲基转移酶具有良好的选择性。化合物28d有效抑制几种白血病细胞系中的细胞增殖,并降低细胞的不对称精氨酸二甲基化水平。作为有效的抑制剂,28d证明了细胞杀伤在细胞周期停滞和凋亡效应以及下调关键混合谱系白血病(MLL)融合靶基因(例如HOXA9MEIS1)中的机制,这反映了类型的关键作用我在MLL白血病中PRMTs。这些研究表明28d作为研究I型PRMT在癌症和其他疾病中的作用的有价值的抑制剂。
更新日期:2017-10-27
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