近日，美国表观遗传学研究中心教授Helai P. Mohammad及其课题组开发出具有抗肿瘤活性的I型PRMT抑制剂，GSK3368715，并与通过MTAP缺失导致的PRMT5抑制协同发挥作用。 2019年6月27日，国际知名学术期刊《癌细胞》发表了这一成果。

I型蛋白精氨酸甲基转移酶(PRMTs)催化蛋白上精氨酸的不对称二甲基化。I型PRMTs及其底物与人类癌症有关，提示抑制I型PRMTs可能为肿瘤治疗提供一种方法。本报告描述了GSK3368715 (EPZ019997)，一种在人类癌症模型中具有抗肿瘤作用的强效可逆型I型PRMT抑制剂。抑制主要的II型PRMT，PRMT5，与GSK3368715联合使用可产生协同抑制癌细胞生长的作用。有趣的是，甲基硫代腺苷磷酸化酶基因(MTAP)的缺失导致代谢物2-甲基硫代腺苷的积累，这是一种内源性的PRMT5抑制剂，与细胞系对GSK3368715的敏感性相关。这些数据为探索MTAP作为患者选择的生物标志物策略提供了理论依据。

附：英文原文

Title: Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

Author: Andrew Fedoriw, Satyajit R. Rajapurkar, Shane O''Brien, Ryan G. Kruger, Olena Barbash, Helai P. Mohammad

Issue&Volume: June 27, 2019

Abstract: Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene ( MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

DOI: https://doi.org/10.1016/j.ccell.2019.05.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30256-9