MAP kinase p38 inhibitors:: Clinical results and an intimate look at their interactions with p38α protein

Mitogen-activated protein kinase p38 is a serine/threonine kinase originally isolated from lipopolysaccharide (LPS) stimulated monocytes. There are four isoforms p38 alpha, p38 beta, p38 gamma, and p38 delta. The most thoroughly studied isoform is p38 alpha, whose activation has been observed in many hematopoietic and non-hematopoietic cell types upon appropriate stimuli. Subsequently, p38 alpha kinase has been shown to be involved in the biosynthesis of TNF alpha and IL-1 beta at the translational and transcriptional level. MAP kinase p38 alpha represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. The discovery and publication of p38 alpha and the pyridinyi-imidazole inhibitor initiated a huge effort by many companies to develop p38a inhibitors as potential treatment for inflammatory diseases. Herein we provide a brief overview of recent reported clinical results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO 323. However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature.