College of Life Sciences, Zhejiang Sci-Tech University , Hangzhou 310018, China.
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
J Med Chem. 2017 Nov 9;60(21):8888-8905. doi: 10.1021/acs.jmedchem.7b01134. Epub 2017 Oct 27.
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 N-(2-((2-chlorophenyl)thio)benzyl)-N-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.
蛋白精氨酸甲基转移酶（PRMTs）在多种生物过程中起着关键作用，PRMTs 的失调与各种人类疾病，尤其是癌症有关。因此，靶向 PRMTs 的小分子对学术功能研究和临床疾病治疗都具有深远的影响。在这里，我们报告了 N-(2-((2-氯苯基)硫)苄基)-N-甲 基乙烷-1,2-二胺（28d，DCPR049_12）的发现，它是一种高效的 I 型 PRMT 抑制剂，对一系列其他甲基转移酶具有良好的选择性。化合物 28d 能有效抑制几种白血病细胞系的增殖，并降低细胞不对称精氨酸二甲基化水平。作为一种有效的抑制剂，28d 表现出细胞周期停滞和凋亡效应的细胞杀伤机制，以及下调关键的混合谱系白血病（MLL）融合靶基因，如 HOXA9 和 MEIS1，这反映了 I 型 PRMTs 在 MLL 白血病中的关键作用。这些研究表明 28d 是一种有价值的抑制剂，可以研究 I 型 PRMTs 在癌症和其他疾病中的作用。
