EPZ020411 is a highly selective, orally bioavailable inhibitor of protein arginine methyltransferase 6 (PRMT6), with an IC50 value of 10nM[1]. PRMT6 regulates gene expression by catalyzing asymmetric dimethylation of histone H3 at arginine 2 (H3R2) and plays critical roles in stem cell function regulation, proliferation control, and differentiation[2]. EPZ020411 exhibits selectivity for PRMT6 over PRMT1 and PRMT8 and is commonly used in studies of epigenetic regulation, cancer, and hearing loss protection[3,4].
In vitro, treatment of mouse microglial BV2 cells with EPZ020411 (1, 10, 20, 50, 100, 1000μM) for 24h showed that concentrations of 50μM and above significantly inhibited BV2 cell viability[5]. EPZ020411 (10μM) treatment of primary mouse cortical neurons co-overexpressing HTT 548-17Q and EGFP-PRMT6 for 24h reversed the PRMT6 overexpression-induced increase in huntingtin (HTT) arginine methylation levels[6]. EPZ020411 (4μM) treatment of mismatch repair (MMR)-proficient colorectal cancer SW480 cells for 24h significantly attenuated the assembly of MutSα and MutSβ complexes[7].
In vivo, EPZ020411 (10mg/kg; once daily) administered via intraperitoneal injection to BALB/c mice bearing subcutaneous xenografts of microsatellite stable (MSS) murine colorectal cancer CT26 cells for 3 weeks significantly inhibited tumor growth[7].
References:
[1] MITCHELL L H, DREW A E, RIBICH S A, et al. Aryl pyrazoles as potent inhibitors of arginine methyltransferases: identification of the first PRMT6 tool compound[J]. ACS Medicinal Chemistry Letters, 2015, 6(6): 655-659.
[2] OKUNO K, AKIYAMA Y, SHIMADA S, et al. Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression[J]. Carcinogenesis, 2019, 40(1): 15-26.
[3] WANG J, XIAO Z, LI P, et al. PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B[J]. Oncogene, 2023, 42(14): 1088-1100.
[4] LI J, LIU C, QIU S, et al. Epigenetic modifications in sensorineural hearing loss: protective mechanisms and therapeutic potential[J]. Current Medical Science, 2025, 45(3): 415-429.
[5] HUA T, KONG E, ZHANG H, et al. PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia[J]. Brain, Behavior, and Immunity, 2024, 118: 101-114.
[6] MIGAZZI A, SCARAMUZZINO C, ANDERSON E N, et al. Huntingtin-mediated axonal transport requires arginine methylation by PRMT6[J]. Cell Reports, 2021, 35(2).
[7] DUAN J, CHEN T, LI Q, et al. Protein arginine methyltransferase 6 enhances immune checkpoint blockade efficacy via the STING pathway in MMR-proficient colorectal cancer[J]. Journal for ImmunoTherapy of Cancer, 2025, 13(3): e010639.
EPZ020411是一种具有高效选择性，且口服生物利用度高的蛋白质精氨酸甲基转移酶6（PRMT6）抑制剂，IC50值为10nM[1]。PRMT6通过对组蛋白H3R2进行精氨酸不对称二甲基化来调节基因表达，在调节干细胞功能、增殖控制和分化等方面发挥关键作用[2]。EPZ020411对PRMT6的选择性远高于PRMT1和PRMT8，通常用于表观遗传调控、癌症和保护听力损失的研究[3,4]。
在体外，EPZ020411（1, 10, 20, 50, 100, 1000μM）处理小鼠小胶质BV2细胞24h，50μM及以上浓度的EPZ020411可显著抑制BV2细胞的活力[5]。EPZ020411（10μM）处理同时过表达了HTT 548-17Q和EGFP-PRMT6的原代小鼠皮层神经元24h，能够逆转PRMT6过表达引起的huntingtin（HTT）蛋白精氨酸甲基化水平升高[6]。EPZ020411（4μM）处理错配修复（MMR）功能完备的结直肠癌SW480细胞24h，显著减弱了MutSα和MutSβ复合物的组装[7]。
在体内，EPZ020411（10mg/kg; once daily）通过腹腔注射治疗携带微卫星稳定（MSS）鼠源结直肠癌细胞CT26皮下移植瘤的BALB/c小鼠3周，能够显著抑制肿瘤的生长[7]。