Novel strategies for inhibition of the p38 MAPK pathway

Trends Pharmacol Sci. 2007 Jun;28(6):286-95. doi: 10.1016/ Epub 2007 May 7.


The p38 subgroup of the mitogen-activated protein kinase superfamily has four isoforms: p38alpha, p38beta, p38delta and p38gamma. Whereas p38alpha is involved in inflammation, proliferation, differentiation and apoptosis, the biological functions of p38beta, p38delta and p38gamma are not understood completely. Many p38alpha inhibitors with diverse chemical structures and modes of protein interaction have been designed on the basis of their ability to compete with ATP for binding to p38alpha. Although some of these inhibitors show anti-inflammatory effects in animal models, they have repeatedly failed in clinical trials, highlighting the need for better approaches to inhibitor design. Here, we discuss alternative strategies that might lead to better p38 inhibitors, including non-ATP-competitive inhibitors and inhibitors that are targeted to other components of the signaling pathway.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • p38 Mitogen-Activated Protein Kinases