Qian Kun, Yan Chunli, Su Hairui, Dang Tran, Zhou Bo, Wang Zhenyu, Zhao Xinyang, Ivanov Ivaylo, Ho Meng-Chiao, Zheng Y George
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia Athens Georgia 30602 USA
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University Atlanta Georgia 30302 USA.
RSC Med Chem. 2020 Sep 30;12(1):95-102. doi: 10.1039/d0md00259c. eCollection 2021 Jan 1.
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)-1-indole-6-carboximidamide), which possessed low-micromolar potency with biochemical IC 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.
蛋白质精氨酸甲基转移酶（PRMTs）是真核生物中重要的表观遗传和翻译后调节剂。PRMTs的失调与多种人类疾病密切相关，尤其是癌症。基于先前报道的带有脒基药效团的PRMT1抑制剂，我们进行了虚拟筛选以鉴定其他与脒相关的结构类似物。随后的酶促测试和表征导致发现了一种先导化合物K313（2-(4-((4-氨基甲脒基苯基)氨基)phenyl)-1-吲哚-6-甲脒），它对人PRMT1具有低微摩尔效力，生化IC50为2.6 μM。在其他一些PRMT亚型如CARM1和PRMT7上观察到有限的选择性。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显著抑制白血病癌细胞的细胞增殖并降低精氨酸不对称二甲基化水平。
