Tumor necrosis factor α (TNFα) has positive and negative roles in human disease. In certain cancers, TNFα is infused locally to promote tumor regression, but dose limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNFα antibodies control inflammation in most patients, but these benefits are offset by cost and tachyphylaxis that develops during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNFα-mediated signaling, uniquely providing a drug development opportunity for cancer and autoimmunity. EDHS-206 is a potent and selective TAK1 inhibitor (IC50 9.5nM) that induces apoptosis in TNFα-dependent manner in cell models of metastatic breast cancer and rheumatoid arthritis. The mechanisms underlying this specificity were revealed in enzymatic and co-crystalization studies and can be found in our publication regarding EDHS-206. Our data show EDHS-206 is an attractive starting point for the development novel inhibitors that greatly sensitize cells to TNFα-induced cell death, broadening the therapeutic efficacy of TNFα for cancer and autoimmune disease.