TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.

中文翻译：

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TAK1 小分子激活剂促进其活性依赖性泛素化和 TRAIL 介导的肿瘤细胞死亡

TAK1 是 NF-κB 信号传导和 RIPK1 的关键调节剂。在TNF信号通路中，TAK1的激活直接介导IKK复合物和RIPK1的磷酸化。在寻找 RIPK1 介导的坏死性凋亡的小分子激活剂时，我们发现了 R406/R788 这两种小分子类似物，可以促进 TAK1 的持续激活。R406 处理通过促进 RIPK1 持续激活，使细胞对 TNF 介导的坏死性凋亡和 RIPK1 依赖性细胞凋亡敏感。使用点击化学和多种生化结合测定，我们表明，R406 处理可通过直接与 TAK1 结合来促进 TAK1 的激活，而不依赖于其原始靶标 Syk 激酶。R406 处理促进 TAK1 泛素化以及激活的 TAK1 与泛素化 RIPK1 的相互作用。最后，我们证明 R406/R788 可以在体外和小鼠模型中促进 TRAIL 的抗癌活性。我们的研究证明了开发小分子 TAK1 激活剂以增强 TRAIL 抗癌疗法效果的可能性。