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

  • Cell Chem Biol. 2017 Aug 17;24(8):1029-1039.e7. doi: 10.1016/j.chembiol.2017.07.011.
Juliane Totzke  1 ,  Deepak Gurbani  2 ,  Rene Raphemot  3 ,  Philip F Hughes  1 ,  Khaldon Bodoor  4 ,  David A Carlson  1 ,  David R Loiselle  1 ,  Asim K Bera  2 ,  Liesl S Eibschutz  1 ,  Marisha M Perkins  3 ,  Amber L Eubanks  3 ,  Phillip L Campbell  5 ,  David A Fox  5 ,  Kenneth D Westover  6 ,  Timothy A J Haystead  7 ,  Emily R Derbyshire  8
Affiliations
  • 1. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
  • 2. Departments of Biochemistry and Radiation Oncology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
  • 3. Department of Chemistry, Duke University, Durham, NC 27710, USA.
  • 4. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Applied Biology, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan.
  • 5. University of Michigan, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Ann Arbor, MI 48109, USA.
  • 6. Departments of Biochemistry and Radiation Oncology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 7. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
  • 8. Department of Chemistry, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 28820959 DOI: 10.1016/j.chembiol.2017.07.011
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.
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