Pharmacophore-based screening of diamidine small molecule inhibitors for protein arginine methyltransferases
Pharmacophore-based screening of diamidine small molecule inhibitors for protein arginine methyltransferases
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DOI：
10.1039/d0md00259c
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发表时间：
2021-01-01
影响因子：
4.1
通讯作者：
Zheng, Y. George
中科院分区：
文献类型：
--
作者：
Qian, Kun;Yan, Chunli;Zheng, Y. George
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因子。PRMT的失调与多种类型的人类疾病，特别是癌症密切相关。基于先前报道的带有联脒药效团的PRMT 1抑制剂，我们进行了虚拟筛选以鉴定另外的脒相关结构类似物。随后的酶测试和表征导致发现了顶级先导化合物K313（2-（4-（（4-甲脒基苯基）氨基）苯基）-1H-吲哚-6-甲脒），其具有低微摩尔效力，对人PRMT 1的生化IC 50为2.6 μ M。相对于一些其他PRMT同种型如CARM 1和PRMT 7，观察到有限的选择性。分子模拟和抑制模式研究表明，K313是一个非经典的非竞争性抑制剂PRMT 1。K313显着抑制细胞增殖，降低白血病癌细胞中精氨酸不对称二甲基化水平。
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 mu M 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.