Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-? Inhibition for Cancer and Autoimmune Disease.

ABSTRACT: Tumor necrosis factor alpha (TNF-?) has both 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 during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-?-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-? stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-?-induced cell death, with general implications for cancer and autoimmune disease treatment.

SUBMITTER: Totzke J 

PROVIDER: S-EPMC5576570 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature