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.

中文翻译：

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Takinib，一种选择性的TAK1抑制剂，拓宽了TNF-α抑制物对癌症和自身免疫性疾病的治疗功效

肿瘤坏死因子α（TNF-α）在人类疾病中具有正作用和负作用。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更广泛的用途。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，但这些益处在长期治疗中会被抵消。TAK1在TNF-α介导的信号传导中充当存活和细胞死亡之间的关键介体。在这里，我们描述了Takinib，一种有效且选择性的TAK1抑制剂，可在类风湿性关节炎和转移性乳腺癌的细胞模型中诱导TNF-α刺激后的凋亡。我们证明Takinib是一种自磷酸化和非磷酸化TAK1抑制剂，可在ATP结合袋中结合并通过减慢TAK1活化的限速步骤而抑制。全面的，