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

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

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1029-1039.e7
JournalCell Chemical Biology
Volume24
Issue number8
DOIs
StatePublished - Aug 17 2017

Keywords

  • autoimmune disease
  • cancer
  • drug discovery
  • enzyme kinetics
  • inflammatory disorders
  • kinase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Drug Discovery
  • Pharmacology

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  • Cite this

    Totzke, J., Gurbani, D., Raphemot, R., Hughes, P. F., Bodoor, K., Carlson, D. A., Loiselle, D. R., Bera, A. K., Eibschutz, L. S., Perkins, M. M., Eubanks, A. L., Campbell, P. L., Fox, D. A., Westover, K. D., Haystead, T. A. J., & Derbyshire, E. R. (2017). Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease. Cell Chemical Biology, 24(8), 1029-1039.e7. https://doi.org/10.1016/j.chembiol.2017.07.011