a Lifespan Cancer Institute, Division of Hematology/Oncology , The Warren Alpert Medical School of Brown University , Providence , RI , USA.
b Department of Medicine , The Warren Alpert Medical School of Brown University , Providence , RI , USA.
Cancer Biol Ther. 2019;20(8):1047-1056. doi: 10.1080/15384047.2019.1595283. Epub 2019 Apr 12.
As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3β inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3β in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of this target and provides the rationale for drug combinations. Emerging data on GSK-3β as a mediator of anticancer immune response also highlight the potential clinical applications of novel selective GSK-3β inhibitors that are entering clinical studies. This manuscript reviews the preclinical and early clinical results with GSK-3β inhibitors and delineates the developmental therapeutics landscape for this potentially important target in cancer therapy.
作为众多代谢和细胞生长信号通路交汇点的激酶，糖原合酶激酶-3β（GSK-3β）是癌症治疗中一个极具吸引力的理想靶点。尽管它参与了与多种恶性肿瘤发病机制相关的途径，但目前尚无选择性 GSK-3β抑制剂被批准用于癌症治疗。GSK-3β 在细胞凋亡、细胞周期、DNA 修复、肿瘤生长、侵袭和转移中的调节作用反映了该靶点的治疗相关性，并为药物联合治疗提供了依据。关于 GSK-3β作为抗癌免疫反应介质的新数据也突出了新型选择性 GSK-3β抑制剂的潜在临床应用，这些抑制剂正在进入临床研究。本文综述了 GSK-3β 抑制剂的临床前和早期临床研究结果，并阐述了该靶点在癌症治疗中的发展治疗学前景。
