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.


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.

MeSH terms

  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • Benzamides / chemistry*
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Down-Regulation / drug effects
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-6 / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Molecular Dynamics Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Synoviocytes / cytology
  • Synoviocytes / drug effects
  • Synoviocytes / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*


  • Benzamides
  • Benzimidazoles
  • Interleukin-6
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • takinib
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7