Targeting Transforming Growth Factor Beta-Activated Kinase 1 as a Therapeutic Strategy in Cancer and Immune Disease

Abstract

<p>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.</p>