Targeting Transforming Growth Factor Beta-Activated Kinase 1 as a Therapeutic Strategy in Cancer and Immune Disease
Tumor necrosis factor (TNF) has positive and negative roles in human disease. In certain cancers, TNF is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF antibodies control inflammation in most patients, but these benefits are offset by cost and tachyphylaxis that develops during chronic treatment. Transforming growth factor beta-activated kinase 1 (TAK1) acts as a key mediator between survival and cell death in TNF-mediated signaling, uniquely providing a drug development opportunity for cancer and autoimmunity. Takinib is a potent and selective TAK1 inhibitor (IC50 9.5nM) that induces apoptosis in a TNF-dependent manner in cell models of metastatic breast cancer and rheumatoid arthritis. The mechanisms underlying this specificity were revealed in enzymatic and co-crystallization studies. These data show that Takinib targets the kinase in the DFG-in conformation and forms direct and water-mediated hydrogen bonds with catalytic residues. Mechanistic studies of TAK1 autophosphorylation demonstrated a substrate-like intermolecular mechanism, during which Takinib treatment slows down the rate-limiting step. Overall, our data show Takinib is an attractive starting point for the development of inhibitors that greatly sensitize cells to TNF-induced cell death, broadening the therapeutic efficacy of TNF for cancer and autoimmune disease.
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