AbMole丨GSK-J4：一种靶向H3K27me3去甲基化酶的多功能抑制剂

GSK-J4（AbMole，M5149）是一种特异性抑制组蛋白H3K27me3去甲基化酶的小分子化合物，其作用机制主要通过调控表观遗传修饰影响下游的信号通路。在细胞实验中，GSK-J4对多种肿瘤细胞系表现出显著的增殖抑制作用：在视网膜母细胞瘤中，1-10 μM浓度可阻滞细胞周期于G2/M期，并通过PI3K/AKT/NF-κB通路诱导细胞凋亡[1]；GSK-J4在非小细胞肺癌A549和H1299细胞中，以剂量依赖性方式抑制TGFβ1诱导的EMT（上皮细胞间质转化）和迁移，且通过Wnt/β-catenin通路发挥作用[2]；在甲状腺癌细胞Cal-62中，GSK-J4的IC50值为1.502 μM，并可协同阿霉素（Doxorubicin）增强抑制效果[3]。

在动物实验中，GSK-J4（CAS No.：1373423-53-0）在裸鼠移植瘤模型（如前列腺癌PC-3/22Rv1、神经母细胞瘤PDX模型）中表现出显著抗肿瘤活性，腹腔注射剂量多为25-50 mg/kg/天[2, 4, 5]，GSK-J4还可减少肿瘤的肺/肝转移灶并降低Ki-67表达。GSK-J4的作用机制还包括：在弥漫性内生性脑桥胶质瘤（DIPG）中通过抑制DNA同源重组修复（表现为γH2AX/53BP1持续高表达）增强细胞周期抑制剂的敏感性[6]；在急性髓系白血病KG-1a细胞中通过PKC-α/p-Bcl2通路诱导凋亡[7]；在KRAS突变肺癌中通过调控谷氨酰胺代谢增强抑制剂的细胞毒性[8]。此外，GSK-J4在炎症模型中（如Lipopolysaccharides 刺激的RAW 264.7巨噬细胞）可抑制NF-κB通路及IL-6/MMP-9等促炎因子释放[9-11]。这些研究数据表明，GSK-J4（AbMole，M5149）作为表观遗传调控工具，在肿瘤、炎症及代谢相关研究中具有广泛的应用潜力。

范例详解

Sci Transl Med. 2018 May 16;10(441):eaao4680.

弗吉尼亚联邦大学的科研人员在上述文章中引用了AbMole的GSK-J4（AbMole，M5149）。科研人员研究发现：神经母细胞瘤细胞对GSK-J4高度敏感，尤其是高危神经母细胞瘤。GSK-J4能通过诱导分化、内质网应激和PUMA上调来抑制肿瘤生长；GSK-J4在小鼠体内对异种移植模型有效；此外，GSK-J4与视黄酸（Retinoic acid）联合使用可增强分化和内质网应激效果。

参考文献及鸣谢

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[4] Pecci, V.; Troisi, F.; Aiello, A.; et al. Targeting of H19/cell adhesion molecules circuitry by GSK-J4 epidrug inhibits metastatic progression in prostate cancer. Cancer cell international 2024, 24 (1), 56.

[5] Lochmann, T. L.; Powell, K. M.; Ham, J.; et al. Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma. Science translational medicine 2018, 10 (441).

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[7] Chu, X.; Zhong, L.; Yu, L.; et al. GSK-J4 induces cell cycle arrest and apoptosis via ER stress and the synergism between GSK-J4 and decitabine in acute myeloid leukemia KG-1a cells. Cancer cell international 2020, 20, 209.

[8] Hong, B. J.; Park, W. Y.; Kim, H. R.; et al. Oncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4-Induced Metabolic and Oxidative Stress. Cancer research 2019, 79 (22), 5849-5859.

[9] Lee, J.; Choi, H.; Park, C.; et al. Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model. International journal of molecular sciences 2021, 22 (24).

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