Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Departments of Biochemistry and Radiation Oncology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Cell Chem Biol. 2017 Aug 17;24(8):1029-1039.e7. doi: 10.1016/j.chembiol.2017.07.011.
Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.
肿瘤坏死因子-α（TNF-α）在人类疾病中既有积极作用，也有消极作用。在某些癌症中，TNF-α被局部注入以促进肿瘤消退，但剂量限制的炎症作用限制了其更广泛的应用。在自身免疫性疾病中，抗 TNF-α 抗体可控制大多数患者的炎症，但在慢性治疗期间，这些益处会被抵消。TAK1 在 TNF-α 介导的信号转导中作为生存和细胞死亡之间的关键介质发挥作用。在这里，我们描述了 Takinib，一种强效和选择性的 TAK1 抑制剂，在类风湿关节炎和转移性乳腺癌的细胞模型中，它在 TNF-α 刺激后诱导细胞凋亡。我们证明 Takinib 是一种能够抑制自身磷酸化和非磷酸化 TAK1 的抑制剂，它结合在 ATP 结合口袋内，通过减缓 TAK1 激活的限速步骤来抑制其活性。总的来说，Takinib 是开发能够使细胞对 TNF-α 诱导的细胞死亡敏感的抑制剂的一个有吸引力的起点，对癌症和自身免疫性疾病的治疗具有普遍意义。
