@article{de0a5f0883564f07995416915675f84a,
title = "Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease",
abstract = "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.",
keywords = "autoimmune disease, cancer, drug discovery, enzyme kinetics, inflammatory disorders, kinase inhibitors",
author = "Juliane Totzke and Deepak Gurbani and Rene Raphemot and Hughes, {Philip F.} and Khaldon Bodoor and Carlson, {David A.} and Loiselle, {David R.} and Bera, {Asim K.} and Eibschutz, {Liesl S.} and Perkins, {Marisha M.} and Eubanks, {Amber L.} and Campbell, {Phillip L.} and Fox, {David A.} and Westover, {Kenneth D.} and Haystead, {Timothy A.J.} and Derbyshire, {Emily R.}",
note = "Funding Information: This work was supported by Welch I1829 (K.D.W.), CPRIT RP140233 (K.D.W.), NIH GM099796 (E.R.D.), and an ORNL Ralph E. Powe Junior Faculty Enhancement Award (E.R.D.). We thank Diana Tomchick, Zhe Chen, the staff at the structural biology laboratory at UT Southwestern Medical Center and at beamline 19ID of Advanced Photon Source for discussions and technical assistance with X-ray data collection and processing. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. K.B. is supported by the Fulbright scholar program and a sabbatical leave from the Jordan University of Science and Technology. We thank Doug Marchuk (Duke University) for providing the FLAG-TNNI3K plasmid and Aaron P. Smith for helpful discussion. A patent disclosure describing Takinib and its analogs has been filed with Duke University by E.R.D. and T.A.J.H. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",
year = "2017",
month = aug,
day = "17",
doi = "10.1016/j.chembiol.2017.07.011",
language = "English (US)",
volume = "24",
pages = "1029--1039.e7",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "8",
}