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. 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.
- Authors:
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); Welch Foundation; Cancer Prevention and Research Institute of Texas (CPRIT); National Institutes of Health (NIH); ORNL Ralph E. Powe Junior Faculty Enhancement Award; Fulbright Scholar Program
- OSTI Identifier:
- 1464982
- Alternate Identifier(s):
- OSTI ID: 1510249
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Published Article
- Journal Name:
- Cell Chemical Biology
- Additional Journal Information:
- Journal Name: Cell Chemical Biology Journal Volume: 24 Journal Issue: 8; Journal ID: ISSN 2451-9456
- Publisher:
- Cell Press - Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; kinase inhibitors; drug discovery; enzyme kinetics; cancer; inflammatory disorders; autoimmune disease
Citation Formats
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., and Derbyshire, Emily R. Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-$α$ Inhibition for Cancer and Autoimmune Disease. United States: N. p., 2017.
Web. doi:10.1016/j.chembiol.2017.07.011.
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. Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-$α$ Inhibition for Cancer and Autoimmune Disease. United States. https://doi.org/10.1016/j.chembiol.2017.07.011
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., and Derbyshire, Emily R. Thu .
"Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-$α$ Inhibition for Cancer and Autoimmune Disease". United States. https://doi.org/10.1016/j.chembiol.2017.07.011.
@article{osti_1464982,
title = {Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-$α$ Inhibition for Cancer and Autoimmune Disease},
author = {Totzke, Juliane and Gurbani, Deepak and Raphemot, Rene and Hughes, Philip F. and Bodoor, Khaldon 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.},
abstractNote = {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.},
doi = {10.1016/j.chembiol.2017.07.011},
journal = {Cell Chemical Biology},
number = 8,
volume = 24,
place = {United States},
year = {Thu Aug 17 00:00:00 EDT 2017},
month = {Thu Aug 17 00:00:00 EDT 2017}
}
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https://doi.org/10.1016/j.chembiol.2017.07.011
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