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Abstract：
TANK-binding kinase 1 (TBK1) regulates various biological processes including, NF-κB signaling, immune response, autophagy, cell division, Ras-mediated oncogenesis, and AKT pro-survival signaling. Enhanced TBK1 activity is associated with autoimmune diseases and cancer, suggesting its role in therapeutic targeting of interferonopathies. In addition, dysregulation of TBK1 activity promotes several inflammatory disorders and oncogenesis. Structural and biochemical study reports provide the molecular process of TBK1 activation and recap the substrate selection about TBK1. This review summarizes recent findings on the molecular mechanisms by which TBK1 is involved in cancer signaling. The IKK-ε and TBK1 are together associated with inflammatory diseases by inducing type I IFNs. Furthermore, TBK1 signaling regulates radiation-induced epithelial-mesenchymal transition by controlling phosphorylation of GSK-3β and expression of Zinc finger E-box-binding homeobox 1, suggesting, TBK1 could be targeted for radiotherapy-induced metastasis therapy. Despite a considerable increase in the list of TBK1 inhibitors, only a few has potential to control cancer. Among them, a compound BX795 is considered a potent and selective inhibitor of TBK1. We discussed the therapeutic potential of small-molecule inhibitors of TBK1, particularly those with high selectivity, which will enable further exploration in the therapeutic management of cancer and inflammatory diseases.
摘要：
TANK结合激酶1（TBK1）调节各种生物过程，包括NF-κB信号,免疫反应，自噬,细胞分裂,Ras介导的肿瘤发生，和AKT促生存信号。TBK1活性增强与自身免疫性疾病和癌症有关，提示其在干扰素病的治疗靶向中的作用。此外,TBK1活性失调可促进多种炎症性疾病和肿瘤发生。结构和生化研究报告提供了TBK1活化的分子过程，并概述了TBK1的底物选择。这篇综述总结了TBK1参与癌症信号传导的分子机制的最新发现。IKK-ε和TBK1通过诱导I型IFN而与炎性疾病相关。此外，TBK1信号通过控制GSK-3β的磷酸化和锌指E盒结合同源盒1的表达来调节辐射诱导的上皮间质转化，TBK1可作为放疗诱导的转移瘤治疗的靶点。尽管TBK1抑制剂的列表有相当大的增加，只有少数人有可能控制癌症。其中,化合物BX795被认为是TBK1的有效和选择性抑制剂。我们讨论了TBK1的小分子抑制剂的治疗潜力，特别是那些具有高选择性的小分子抑制剂，这将有助于进一步探索癌症和炎性疾病的治疗管理。
