EPZ015666

EPZ015666 is a novel and selective inhibitor of protein arginine methyltransferase 5 (PRMT5)^[1] with an IC₅₀ value <10nM^[2]. a key member of the protein arginine methyltransferase (PRMTs) family^[3]. PRMT5 plays a critical role in various cellular processes, including transcriptional repression, RNA splicing, and signal transduction^[4]. EPZ015666 demonstrates potent inhibitory activity against PRMT5 in multiple cancer types^[5].

In vitro, treatment of Retinoblastoma (RB) cells with EPZ015666 (0–30μM) for 24–72h significantly inhibited cell proliferation in a time-and dose-dependent manner. This was accompanied by a reduction in Cyclin-Dependent Kinase 2 (CDK2) protein levels and an increase in the expression of key tumor suppressor proteins Cyclin-Dependent Kinase Inhibitor 1A, CDK-interacting protein 1 (P21), Cyclin-Dependent Kinase Inhibitor 1B (P27), andTumor Protein P53 ( P53) ^[1]. In U14 cells, exposure to EPZ015666 (10μM) did not affect cell viability or proliferation but suppressed PD-L1 expression^[6]. Similarly, treatment of iSLK.RGB cells with EPZ015666 (50μM) for 48h resulted in marked inhibition of cell proliferation ^[7].

In vivo, administration of EPZ015666 (25 mg/kg/day and 75 mg/kg/day) via intraperitoneal injection for 12 days in mice bearing U14 cell xenografts resulted in a reduction in tumor volume, tumor size, and tumor weight in a dose-dependent manner ^[6]. Furthermore, oral treatment with EPZ015666 (150mg/kg of body weight twice a day) for 21 days in a xenograft mouse model using Retinoblastoma cells (Y79 cells) significantly suppressed tumor growth ^[1].

References:
[1] Liu X, He J, Mao L, Zhang Y, Cui W, Duan S, Jiang A, Gao Y, Sang Y, Huang G. EPZ015666, a selective protein arginine methyltransferase 5 (PRMT5) inhibitor with an antitumour effect in retinoblastoma. Exp Eye Res. 2021 Jan;202:108286.
[2] Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, Duncan KW. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015 Jun;11(6):432-7.
[3] Zhang S, Ma Y, Hu X, Zheng Y, Chen X. Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. J Cell Mol Med. 2019 Feb;23(2):1333-1342.
[4] Liu C, Zou W, Nie D, Li S, Duan C, Zhou M, Lai P, Yang S, Ji S, Li Y, Mei M, Bao S, Jin Y, Pan J. Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML. Cell Metab. 2022 Jun 7;34(6):818-835.e7.
[5] Zheng J, Li B, Wu Y, Wu X, Wang Y. Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies. J Med Chem. 2023 Jul 13;66(13):8407-8427. 
[6] Jiang Y, Yuan Y, Chen M, Li S, Bai J, Zhang Y, Sun Y, Wang G, Xu H, Wang Z, Zheng Y, Nie H. PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression. Theranostics. 2021 Aug 28;11(18):9162-9176.
[7] Niu D, Ma Y, Ren P, Chang S, Li C, Jiang Y, Han C, Lan K. Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation. PLoS Pathog. 2024 Sep 10;20(9):e1012535.

EPZ015666是一种新型的选择性蛋白精氨酸甲基转移酶5（PRMT5）抑制剂^[1]，IC₅₀值< 10nM^[2] 。PRMT5是蛋白质精氨酸甲基转移酶(PRMTs)家族的主要成员[3] ，在转录抑制、RNA剪接和信号转导等细胞过程中发挥重要作用^[4]，EPZ015666可抑制多种癌症中的PRMT5^[5]。

在体外，EPZ015666（0-30μM）处理人视网膜母细胞瘤（RB）细胞24-72h，以时间和剂量依赖性方式显著抑制了细胞增殖，并且细胞周期蛋白依赖性激酶 2（CDK2）的蛋白水平降低，而重要的抗癌因子细胞周期蛋白依赖性激酶抑制因子1A （P21）、细胞周期蛋白依赖性激酶抑制因子1B（P27）和肿瘤蛋白P53（P53）的蛋白水平升高^[1]。用EPZ015666（10μM）处理U14细胞，对细胞的活力和增殖没有影响，但抑制了PD-L1的表达^[6]。用EPZ015666（50μM）处理iSLK.RGB细胞48h，细胞增殖受到明显抑制^[7]。

在体内，EPZ015666（25mg/kg/day and 75mg/kg/day）通过腹腔注射治疗U14细胞异种移植小鼠12天，可以减少小鼠的肿瘤体积、肿瘤大小和肿瘤重量，并且这种治疗作用具有剂量依赖性^[6]。EPZ015666（150mg/kg of body weight twice a day）通过口服治疗RB 细胞（Y79 细胞） 细胞异种移植小鼠21天，抑制了小鼠的肿瘤生长^[1]。