Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease. Issue 8 (17th August 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Cell chemical biology. Volume 24:Issue 8(2017)
• Page Start: 1029
• Page End: 1039.e7
• Publication Date: 2017-08-17
• Subjects: kinase inhibitors -- drug discovery -- enzyme kinetics -- cancer -- inflammatory disorders -- autoimmune disease; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.07.011
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Here, 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. Graphical Abstract: Highlights: Identification of Takinib as a potent (IC50 9.5 nM) and selective TAK1 inhibitor X-ray structure reveals binding of Takinib deep in the ATP-binding pocket of TAK1 Enzymatic studies demonstrate a substrate-like autophosphorylation mechanism Takinib induces TNF-α -dependent cell death in rheumatoid arthritis and breast cancer Abstract : Totzke et al. combine enzymatic and cell biological methods to identify a novel potent and selective TAK1 inhibitor that induces apoptosis in a TNF-α-dependent manner in rheumatoid arthritis and breast cancer models and reveals a substrate-like mechanism for autophosphorlyation for TAK1.