Novel strategies for inhibition of the p38 MAPK pathway

The p38 subgroup of the mitogen-activated protein kinase superfamily has four isoforms: p38α, p38β, p38δ and p38γ. Whereas p38α is involved in inflammation, proliferation, differentiation and apoptosis, the biological functions of p38β, p38δ and p38γ are not understood completely. Many p38α 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 p38α. 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.