TAK1 selective inhibition: state of the art and future opportunities

Future Med Chem. 2015;7(1):23-33. doi: 10.4155/fmc.14.138.


The mitogen activated protein kinase kinase kinase transforming growth factor-β-activated kinase 1 (TAK1) has emerged as an interesting therapeutic target for inflammatory diseases and cancer. TAK1 is a tightly regulated kinase that represents a key signaling node in cellular responses to inflammatory stimuli, modulating both expression of inflammatory mediators and cell death. The first inhibitors described for TAK1 exploit the active site cysteine residue found in this kinase, but more recently both type I ATP hinge-binding inhibitors and type II DFG-out inhibitors have been described. This article will review the emerging role of TAK1 kinase in inflammation, the current state of the art for small molecule inhibitor development and opportunities for chemical biology approaches.

Keywords: DFG-out; MAPK; NFκB; TAK1; covalent inhibitor; inflammation; kinase.

Publication types

  • Review

MeSH terms

  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Dynamics Simulation
  • NF-kappa B / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • Signal Transduction / drug effects


  • DFG peptide
  • NF-kappa B
  • Oligopeptides
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7