GSK3368715 dihydrochloride is a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models[1]. GSK3368715 decrease the PRMT1-specific histone mark H4R3me2a without affecting the methylation of H3R17me2a (by CARM1 and PRMT6) or PABP1 (by CARM1)[3].
In vitro, treatment with 6µM GSK3368715 for 24 hours inhibited cGAS methylation levels in HEK293T cells[1]. Treatment with 6μM GSK3368715 for 48 hours increased the phosphorylation level of IRF3 in HeLa cells expressing wild-type cGAS[1]. The growth half-maximal inhibitory concentration (gIC50) values of GSK3368715 against MM cell lines ranged from 0.021µM to 14.405µM[2]. GSK3368715 at concentrations ranging from 0.12 to 1μM reduced colony growth in a dose-dependent manner when MDA-MB-468 cells were cultured on plastic for 9 days[3].
In vivo, oral administration of GSK3368715 at 80mg/kg once daily for 14 days resulted in elevated mPD-L1 expression across multiple organs and tissues in six-weeks old BALB/c female mice[1]. Treatment with GSK3368715 (80mg/kg; orally; once daily for 5 days) in nude mice bearing MDA-MB-468–derived xenografts led to increased global monomethylation, decreased H4R3me2a levels in tumors, and a significant delay in tumor growth[3].
References:
[1] Liu J, Bu X, Chu C, et al. PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity. Nat Commun. 2023;14(1):2806.
[2] Hussain T, Awasthi S, Shahid F, Yi SS, Sahni N, Aldaz CM. Therapeutic potential of PRMT1 as a critical survival dependency target in multiple myeloma. BMC Cancer. 2025;25(1):1704.
[3] Suresh S, Huard S, Brisson A, et al. PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer. Cancers (Basel). 2022;14(2):306.
GSK3368715 dihydrochloride是一种有效的、可逆的I型PRMT抑制剂，在人类癌症模型中具有抗肿瘤作用[1]。GSK3368715降低了PRMT1特异性组蛋白标记H4R3me2a，但不影响H3R17me2a（CARM1和PRMT6）或PABP1（CARM1）的甲基化。
体外实验中，6µM GSK3368715处理24小时可抑制HEK293T细胞的cGAS甲基化水平。6μM GSK3368715处理48小时后，表达野生型cGAS的HeLa细胞中IRF3的磷酸化水平升高。GSK3368715对多发性骨髓瘤细胞株的半数生长抑制浓度（gIC50）为0.021µM到14.405µM。在塑料培养皿上培养9天的MDA-MB-468细胞中，0.12–1μM的GSK3368715以剂量依赖性方式抑制了细胞克隆形成的能力。
体内实验中，口服GSK3368715，剂量为80mg/kg，每天1次，连续14天，可导致6周龄BALB/c雌性小鼠多器官和组织中mPD-L1表达升高。在携带 MDA-MB-468 来源异种移植瘤的裸鼠中，GSK3368715（80mg/kg；口服；每日一次；连续5天）治疗导致肿瘤内全局单甲基化水平增加，H4R3me2a 水平下降，并显著延缓了肿瘤生长。