Novel strategies for inhibition of the p38 MAPK pathway

The p38 subgroup of the m itogen -activated protein kinase superfamily has four isoforms: p38 alpha, p38 beta, p38 delta and p38 gamma. Whereas p38 alpha is involved in inflammation, proliferation, differentiation and apoptosis, the biological functions of p38 beta, p38 delta and p38 gamma are not understood completely. Many p38(x 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 p38 alpha. 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.