GSK126 (GSK2816126A, GSK2816126) is a highly selective EZH2 methyltransferase inhibitor with IC50 12.6-17.4nM in vitro (MM cells), and IC50 9.9nM in vivo (Male *ApoE-/-* mice) [1,2]. Published researches show that targeting EZH2 by GSK126 is beneficial to reduces atherosclerotic plaque, and suppresses carcinogenesis, cell migration, and angiogenesis[3].
In vitro, GSK126 (5µM; 36h; 37˚C) pharmacologically inhibits EZH2, reduces lipid transportation and monocyte adhesion during atherogenesis by increasing the expression levels of ATP-binding cassette transporter A1 and suppressing vascular cell adhesion molecule 1 in human THP-1 cells[2]. GSK126 (5, 10μM; 48h) suppress colorectal cancer by regulating macrophage polarization in the tumor microenvironment in a MC38 and RAW264.7 cells based 3D culture model[4]. GSK126 (1nM-10μM; 7 days) suppress HTLV-1-infected CD4+ T cell proliferation and hyperimmune response in HTLV-1-associated myelopathy[5].
In vivo, GSK126-treated(50mg/kg/day; 10 weeks; i.p) mice showed significantly decreased atherosclerotic plaques[2]. GSK126 (100mg/kg; 1 month; i.p) inhibits the growth of colorectal cancer cells/xenografts in BALB/c nu/nu model[6]. GSK126(1nM-100μM; 3 times a week; i.p) enhances antigen presentation, antitumor immunity, and circumvents anti-PD-1 resistance in head and neck cancer C57BL/6 mice model[7].
References:
[1] Zeng, Delong et al. “Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells.” *Oncotarget* vol. 8,2 (2017): 3396-3411. doi:10.18632/oncotarget.13773
[2] Wei, Xianjing et al. “Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E-deficient mice.” *Experimental and therapeutic medicine*vol. 22,2 (2021): 841. doi:10.3892/etm.2021.10273
[3] Chen, Ya-Tian et al. “The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A.” *Cancer chemotherapy and pharmacology* vol. 77,4 (2016): 757-65. doi:10.1007/s00280-016-2990-1
[4] Li, Chen et al. “EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment.” *Frontiers in immunology* vol. 13 857808. 1 Apr. 2022, doi:10.3389/fimmu.2022.857808
[5] Koseki, Akihito et al. “EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy.” *Frontiers in microbiology* vol. 14 1175762. 12 Jun. 2023, doi:10.3389/fmicb.2023.1175762
[6] Yang, Liu et al. “PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression.” *Theranostics* vol. 11,8 3742-3759. 27 Jan. 2021, doi:10.7150/thno.53023
[7]Zhou, Liye et al. “Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research vol. 26,1 (2020): 290-300. doi:10.1158/1078-0432.CCR-19-1351
GSK126(GSK2816126A, GSK2816126)是一种高选择性EZH2甲基转移酶抑制剂，在体外的IC50为12.6~17.4nM；在体内的IC50为9.9nM[1,2]。研究表明，GSK126靶向EZH2有利于减少动脉粥样硬化斑块，抑制癌变、细胞迁移和血管生成[3]。
体外，GSK126(5µM; 36h; 37˚C)药理抑制EZH2，通过增加ATP结合盒转运蛋白A1的表达水平和抑制血管细胞粘附分子1在人THP-1细胞中减少动脉粥样硬化过程中的脂质转运和单核细胞粘附[2]。GSK126(5,10μM; 48h)在基于MC38和RAW264.7细胞的3D模型中通过调节肿瘤微环境中的巨噬细胞极化来抑制结直肠癌[4]。GSK126(1nM-10μM; 7天)抑制HTLV-1感染的CD4+ T细胞增殖和HTLV-1相关脊髓病的超免疫反应[5]。
在体内，GSK126处理(50mg/kg/天; 10周; 腹腔注射）小鼠显示动脉粥样硬化斑块明显减少[2]。GSK126(100mg/kg; 1个月; 腹腔注射）抑制BALB/c nu/nu小鼠中结直肠癌细胞/异种移植物的生长[6]。GSK126(1nM-100μM; 每周3次; 腹腔注射）在头颈癌C57BL/6小鼠模型中增强抗原呈递、抗肿瘤免疫和规避抗PD-1耐药性[7]。