GSK-J4作為靶向H3K27me3去甲基化酶多功能抑制劑的作用機(jī)制及應(yīng)用

GSK-J4（AbMole，M5149）是一種特異性抑制組蛋白H3K27me3去甲基化酶的小分子化合物，其作用機(jī)制主要通過(guò)調(diào)控表觀遺傳修飾影響下游的信號(hào)通路。在細(xì)胞實(shí)驗(yàn)中，GSK-J4對(duì)多種腫瘤細(xì)胞系表現(xiàn)出顯著的增殖抑制作用：在視網(wǎng)膜母細(xì)胞瘤中，1-10 μM濃度可阻滯細(xì)胞周期于G2/M期，并通過(guò)PI3K/AKT/NF-κB通路誘導(dǎo)細(xì)胞凋亡[1]；GSK-J4在非小細(xì)胞肺癌A549和H1299細(xì)胞中，以劑量依賴性方式抑制TGFβ1誘導(dǎo)的EMT（上皮細(xì)胞間質(zhì)轉(zhuǎn)化）和遷移，且通過(guò)Wnt/β-catenin通路發(fā)揮作用[2]；在甲狀腺癌細(xì)胞Cal-62中，GSK-J4的IC50值為1.502 μM，并可協(xié)同阿霉素（Doxorubicin）增強(qiáng)抑制效果[3]。

動(dòng)物實(shí)驗(yàn)中，GSK-J4（CAS No.：1373423-53-0）在裸鼠移植瘤模型（如前列腺癌PC-3/22Rv1、神經(jīng)母細(xì)胞瘤PDX模型）中表現(xiàn)出顯著抗腫瘤活性，腹腔注射劑量多為25-50 mg/kg/天[2, 4, 5]，GSK-J4還可減少腫瘤的肺/肝轉(zhuǎn)移灶并降低Ki-67表達(dá)。GSK-J4的作用機(jī)制還包括：在彌漫性內(nèi)生性腦橋膠質(zhì)瘤（DIPG）中通過(guò)抑制DNA同源重組修復(fù)（表現(xiàn)為γH2AX/53BP1持續(xù)高表達(dá)）增強(qiáng)細(xì)胞周期抑制劑的敏感性[6]；在急性髓系白血病KG-1a細(xì)胞中通過(guò)PKC-α/p-Bcl2通路誘導(dǎo)凋亡[7]；在KRAS突變肺癌中通過(guò)調(diào)控谷氨酰胺代謝增強(qiáng)抑制劑的細(xì)胞毒性[8]。此外，GSK-J4在炎癥模型中（如Lipopolysaccharides 刺激的RAW 264.7巨噬細(xì)胞）可抑制NF-κB通路及IL-6/MMP-9等促炎因子釋放[9-11]。這些研究數(shù)據(jù)表明，GSK-J4（AbMole，M5149）作為表觀遺傳調(diào)控工具，在腫瘤、炎癥及代謝相關(guān)研究中具有廣泛的應(yīng)用潛力。

范例詳解
Sci Transl Med. 2018 May 16;10(441):eaao4680.
弗吉尼亞聯(lián)邦大學(xué)的科研人員在上述文章中引用了AbMole的GSK-J4（AbMole，M5149）�？蒲腥藛T研究發(fā)現(xiàn)：神經(jīng)母細(xì)胞瘤細(xì)胞對(duì)GSK-J4高度敏感，尤其是高危神經(jīng)母細(xì)胞瘤。GSK-J4能通過(guò)誘導(dǎo)分化、內(nèi)質(zhì)網(wǎng)應(yīng)激和PUMA上調(diào)來(lái)抑制腫瘤生長(zhǎng)；GSK-J4在小鼠體內(nèi)對(duì)異種移植模型有效；此外，GSK-J4與視黃酸（Retinoic acid）https://www.abmole.cn/products/retinoic-acid.html聯(lián)合使用可增強(qiáng)分化和內(nèi)質(zhì)網(wǎng)應(yīng)激效果。

參考文獻(xiàn)及鳴謝
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[2] Xu, D.; Wang, M.; Wu, M.; et al. Anti-tumor effects and mechanism of the histone demethylase inhibitor GSK-J4 in non-small cell lung cancer cells. Medical oncology (Northwood, London, England) 2025, 43 (2), 86.
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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.
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