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

Totzke, Juliane; Gurbani, Deepak; Raphemot, Rene; Hughes, Philip F.; Bodoor, Khaldon; Carlson, David A.; Loiselle, David R.; Bera, Asim K.; Eibschutz, Liesl S.; Perkins, Marisha M.; Eubanks, Amber L.; Campbell, Phillip L.; Fox, David A.; Westover, Kenneth D.; Haystead, Timothy A. J.; Derbyshire, Emily R.

doi:10.1016/j.chembiol.2017.07.011

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

Journal Article · Thu Aug 17 00:00:00 EDT 2017 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2017.07.011· OSTI ID:1464982

Totzke, Juliane; Gurbani, Deepak; Raphemot, Rene; Hughes, Philip F.; Bodoor, Khaldon; Carlson, David A.; Loiselle, David R.; Bera, Asim K.; Eibschutz, Liesl S.; Perkins, Marisha M.; Eubanks, Amber L.; Campbell, Phillip L.; Fox, David A.; Westover, Kenneth D.; Haystead, Timothy A. J.; Derbyshire, Emily R.

Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α 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-α-mediated signaling. In this paper, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α 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-α-induced cell death, with general implications for cancer and autoimmune disease treatment.

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Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1464982

Alternate ID(s):: OSTI ID: 1510249

Journal Information:: Cell Chemical Biology, Journal Name: Cell Chemical Biology Journal Issue: 8 Vol. 24; ISSN 2451-9456

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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