GSK-J4作為靶向H3K27me3去甲基化酶多功能抑制劑的作用機制及應用
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，其作用機制主要通過調控表觀遺傳修飾影響下游的信號通路。在細胞實驗中，GSK-J4對多種腫瘤細胞系表現出顯著的增殖抑制作用：在視網膜母細胞瘤中，1-10 μM濃度可阻滯細胞周期于G2/M期，并通過PI3K/AKT/NF-κB通路誘導細胞凋亡[1]；GSK-J4在非小細胞肺癌A549和H1299細胞中，以劑量依賴性方式抑制TGFβ1誘導的EMT（上皮細胞間質轉化）和遷移，且通過Wnt/β-catenin通路發(fā)揮作用[2]；在甲狀腺癌細胞Cal-62中，GSK-J4的IC50值為1.502 μM，并可協(xié)同阿霉素（Doxorubicin）增強抑制效果[3]。
動物實驗中，GSK-J4（CAS No.：1373423-53-0）在裸鼠移植瘤模型（如前列腺癌PC-3/22Rv1、神經母細胞瘤PDX模型）中表現出顯著抗腫瘤活性，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/肝轉移灶并降低Ki-67表達。GSK-J4的作用機制還包括：在彌漫性內生性腦橋膠質瘤（DIPG）中通過抑制DNA同源重組修復（表現為γH2AX/53BP1持續(xù)高表達）增強細胞周期抑制劑的敏感性[6]；在急性髓系白血病KG-1a細胞中通過PKC-α/p-Bcl2通路誘導凋亡[7]；在KRAS突變肺癌中通過調控谷氨酰胺代謝增強抑制劑的細胞毒性[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]。這些研究數據表明，GSK-J4（AbMole，M5149）作為表觀遺傳調控工具，在腫瘤、炎癥及代謝相關研究中具有廣泛的應用潛力。
范例詳解
Sci Transl Med. 2018 May 16;10(441):eaao4680.
弗吉尼亞聯邦大學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：神經母細胞瘤細胞對GSK-J4高度敏感，尤其是高危神經母細胞瘤。GSK-J4能通過誘導分化、內質網應激和PUMA上調來抑制腫瘤生長；GSK-J4在小鼠體內對異種移植模型有效；此外，GSK-J4與視黃酸（Retinoic acid）https://www.abmole.cn/products/retinoic-acid.html聯合使用可增強分化和內質網應激效果。
參考文獻及鳴謝
[1] Zhang, Y.; Wu, W.; Xu, C.; et al. Antitumoral Potential of the Histone Demethylase Inhibitor GSK-J4 in Retinoblastoma. Investigative ophthalmology & visual science 2024, 65 (2), 34.
[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.
[3] Lin, B.; Lu, B.; Hsieh, I. Y.; et al. Synergy of GSK-J4 With Doxorubicin in KRAS-Mutant Anaplastic Thyroid Cancer. Frontiers in pharmacology 2020, 11, 632.
[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).
[6] Katagi, H.; Louis, N.; Unruh, D.; et al. Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 2019, 25 (18), 5572-5583.
[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).
[10] Donas, C.; Carrasco, M.; Fritz, M.; et al. The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. Journal of autoimmunity 2016, 75, 105-117.
[11] Jun, Z.; Xinmeng, J.; Yue, L.; et al. Jumonji domain containing-3 (JMJD3) inhibition attenuates IL-1beta-induced chondrocytes damage in vitro and protects osteoarthritis cartilage in vivo. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2020, 69 (7), 657-666.
動物實驗中，GSK-J4（CAS No.：1373423-53-0）在裸鼠移植瘤模型（如前列腺癌PC-3/22Rv1、神經母細胞瘤PDX模型）中表現出顯著抗腫瘤活性，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/肝轉移灶并降低Ki-67表達。GSK-J4的作用機制還包括：在彌漫性內生性腦橋膠質瘤（DIPG）中通過抑制DNA同源重組修復（表現為γH2AX/53BP1持續(xù)高表達）增強細胞周期抑制劑的敏感性[6]；在急性髓系白血病KG-1a細胞中通過PKC-α/p-Bcl2通路誘導凋亡[7]；在KRAS突變肺癌中通過調控谷氨酰胺代謝增強抑制劑的細胞毒性[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]。這些研究數據表明，GSK-J4（AbMole，M5149）作為表觀遺傳調控工具，在腫瘤、炎癥及代謝相關研究中具有廣泛的應用潛力。
范例詳解
Sci Transl Med. 2018 May 16;10(441):eaao4680.
弗吉尼亞聯邦大學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：神經母細胞瘤細胞對GSK-J4高度敏感，尤其是高危神經母細胞瘤。GSK-J4能通過誘導分化、內質網應激和PUMA上調來抑制腫瘤生長；GSK-J4在小鼠體內對異種移植模型有效；此外，GSK-J4與視黃酸（Retinoic acid）https://www.abmole.cn/products/retinoic-acid.html聯合使用可增強分化和內質網應激效果。
參考文獻及鳴謝
[1] Zhang, Y.; Wu, W.; Xu, C.; et al. Antitumoral Potential of the Histone Demethylase Inhibitor GSK-J4 in Retinoblastoma. Investigative ophthalmology & visual science 2024, 65 (2), 34.
[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.
[3] Lin, B.; Lu, B.; Hsieh, I. Y.; et al. Synergy of GSK-J4 With Doxorubicin in KRAS-Mutant Anaplastic Thyroid Cancer. Frontiers in pharmacology 2020, 11, 632.
[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).
[6] Katagi, H.; Louis, N.; Unruh, D.; et al. Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 2019, 25 (18), 5572-5583.
[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).
[10] Donas, C.; Carrasco, M.; Fritz, M.; et al. The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. Journal of autoimmunity 2016, 75, 105-117.
[11] Jun, Z.; Xinmeng, J.; Yue, L.; et al. Jumonji domain containing-3 (JMJD3) inhibition attenuates IL-1beta-induced chondrocytes damage in vitro and protects osteoarthritis cartilage in vivo. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2020, 69 (7), 657-666.
標簽：
神經母細胞瘤
