GSK3326595 (EPZ015938) is an orally active, effective, and selective inhibitor of protein arginine methyltransferase 5 (PRMT5) [1]. PRMT5 is an enzyme that methylates arginine in a protein crucial for tumor growth and development [2]. GSK3326595 can inhibit the proliferation of cancer cells and can be used in the research of relapsed/refractory mantle cell lymphoma [3-4].
In vitro, GSK3326595 (100nM; 12h) treatment induces M1-type polarization in peritoneal macrophages by inhibiting PRMT5 [5]. GSK3326595 (0 - 10μM; 3, 5 days) treatment significantly inhibits the proliferation and PRMT5 activity of B16 tumor cells and T cells [6].
In vivo, GSK3326595 (5mg/kg/day; three times a week for 9 weeks; i.p.) treatment significantly increases the levels of triglycerides and fatty acid synthase (FASN) transcripts in the liver of high cholesterol-low density lipoprotein (LDL) receptor knockout mice without affecting atherosclerosis [5]. GSK3326595 (50, 100mg/kg/day; 2 weeks) oral treatment can significantly reduce tumor multiplicity, liver weight, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the MYC-ON model mice [7].
References:
[1] Castillo-Aguilera O, Depreux P, Halby L, Arimondo PB, Goossens L. DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge. Biomolecules. 2017;7(1):3. Published 2017 Jan 5.
[2] Siu L L, Rasco D W, Vinay S P, et al. METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours[J]. Annals of Oncology, 2019, 30: v159.
[3] Gerhart, S.V., Kellner, W.A., Thompson, C., et al. Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci. Rep. 8(1), 9711 (2018)
[4] Vieito M, Moreno V, Spreafico A, et al. Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in advanced solid tumors[J]. Clinical Cancer Research, 2023, 29(18): 3592-3602.
[5] Zhang Y, Verwilligen R A F, Van Eck M, et al. PRMT5 inhibition induces pro‐inflammatory macrophage polarization and increased hepatic triglyceride levels without affecting atherosclerosis in mice[J]. Journal of Cellular and Molecular Medicine, 2023, 27(8): 1056-1068.
[6] Chen S, Hou J, Jaffery R, et al. MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors[J]. Journal for immunotherapy of cancer, 2024, 12(9): e009600.
[7] Luo Y, Gao Y, Liu W, Yang Y, Jiang J, Wang Y, Tang W, Yang S, Sun L, Cai J, Guo X, Takahashi S, Krausz KW, Qu A, Chen L, Xie C, Gonzalez FJ. Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma. Hepatology. 2021 Oct;74(4):1932-1951.
GSK3326595 (EPZ015938) 是一种具有口服活性的、有效的、选择性protein arginine methyltransferase 5（PRMT5）抑制剂 [1]。PRMT5是一种对肿瘤生长和发展至关重要的蛋白质中的精氨酸甲基化的酶 [2]。GSK3326595能够抑制癌细胞增殖，可用于复发/难治性套细胞淋巴瘤的研究 [3-4]。
在体外，GSK3326595（100nM; 12h）处理通过抑制PRMT5使腹膜巨噬细胞引发IFN-γ诱导的M1型极化 [5]。GSK3326595（0-10μM; 3, 5 days）处理能够显著抑制B16肿瘤细胞和T细胞的增殖和PRMT5活性 [6]。
在体内，GSK3326595（5mg/kg/day; three times a week for 9 weeks; i.p.）治疗显著增加了高胆固醇血症低密度脂蛋白（LDL）受体敲除小鼠的肝脏甘油三酯和脂肪酸合酶（FASN）转录物水平而不影响动脉粥样硬化 [5]。GSK3326595（50, 100mg/kg/day; 2 weeks）口服治疗可显著降低髓细胞增生启动（MYC-ON）模型小鼠的肿瘤多重性，肝脏重量以及血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平 [7]。