Protein arginine methyltransferases (PRMTs) are essential epigenetic and post-translational regulators in eukaryotic organisms. Dysregulation of PRMTs is intimately related to multiple types of human diseases, particularly cancer. Based on the previously reported PRMT1 inhibitors bearing the diamidine pharmacophore, we performed virtual screening to identify additional amidine-associated structural analogs. Subsequent enzymatic tests and characterization led to the discovery of a top lead K313 (2-(4-((4-carbamimidoylphenyl)amino)phenyl)-1H-indole-6-carboximidamide), which possessed low-micromolar potency with biochemical IC₅₀ of 2.6 μM for human PRMT1. Limited selectivity was observed over some other PRMT isoforms such as CARM1 and PRMT7. Molecular modeling and inhibition pattern studies suggest that K313 is a nonclassic noncompetitive inhibitor to PRMT1. K313 significantly inhibited cell proliferation and reduced the arginine asymmetric dimethylation level in the leukaemia cancer cells.

中文翻译：

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基于药效团的蛋白质精氨酸甲基转移酶二脒小分子抑制剂筛选

蛋白质精氨酸甲基转移酶 (PRMT) 是真核生物中必不可少的表观遗传和翻译后调节因子。PRMTs 的失调与多种类型的人类疾病密切相关，尤其是癌症。基于先前报道的带有二脒药效团的 PRMT1 抑制剂，我们进行了虚拟筛选，以确定其他脒相关的结构类似物。随后的酶促测试和表征导致发现了顶部先导 K313 (2-(4-((4-carbamiimidoylphenyl)amino)phenyl)-1 H -indole-6-carboximidamide)，它具有低微摩尔效力和生化 IC ₅₀对于人类 PRMT1，为 2.6 μM。观察到对一些其他 PRMT 同种型（如 CARM1 和 PRMT7）的选择性有限。分子建模和抑制模式研究表明 K313 是 PRMT1 的非经典非竞争性抑制剂。K313显着抑制细胞增殖并降低白血病癌细胞中的精氨酸不对称二甲基化水平。