TAK1是NF-κB信号通路和RIPK1的关键调节因子。在TNF信号通路中，TAK1的活化直接介导了IKK复合物和RIPK1的磷酸化。在寻找RIPK1介导的坏死样细胞死亡小分子活化剂的过程中，我们发现了两种小分子类似物R406/R788，它们能够促进TAK1的持续激活。R406处理使得细胞对TNF介导的坏死样细胞死亡以及依赖于RIPK1的凋亡敏感，通过促进RIPK1的持续激活。通过点击化学和多种生化结合实验，我们证明R406处理通过直接结合到TAK1促进TAK1的活化，而与其原始靶标Syk激酶无关。R406处理促进了TAK1的泛素化并增强了活化的TAK1与泛素化的RIPK1之间的相互作用。最后，我们证明R406/R788能够在体外和小鼠模型中促进TRAIL的抗癌活性。我们的研究表明了开发小分子TAK1激活剂以增强TRAIL的抗癌治疗效果的可能性。

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.