Inhibition of p38 MAP kinase as a therapeutic strategy

Since the discovery of p38 MAP kinase in 1994, our understanding of its bio logy has progressed dramatically. The key advances include (1) identificati on of p38 MAP kinase homologs and protein kinases that act upstream and dow nstream from p38 MAP kinase, (2) identification of interesting and potentia lly important substrates, (3) elucidation of the role of p38 MAP kinase in cellular processes and (4) the establishment of the mechanism by which the pyridinylimidazole p38 MAP kinase inhibitors inhibit enzyme activity. It is now known that there are four members of the p38 MAP kinase family. They d iffer in their tissue distribution, regulation of kinase activation and sub sequent phosphorylation of downstream substrates. They also differ in terms of their sensitivities toward the p38 MAP kinase inhibitors. The best-stud ied isoform is p38 alpha, whose activation has been observed in many hemato poietic and non-hematopoietic cell types upon treatment with appropriate st imuli. The pyridinylimidazole compounds, exemplified by SB 203580, were ori ginally prepared as inflammatory cytokine synthesis inhibitors that subsequ ently were found to be selective inhibitors of p38 MAP kinase. SB 203580 in hibits the catalytic activity of p38 MAP kinase by competitive binding in t he ATP pocket. X-ray crystallographic studies of the target enzyme complexe d with inhibitor reinforce the observations made from site-directed mutagen esis studies, thereby providing a molecular basis for understanding the kin ase selectivity of these inhibitors. The p38 MAP kinase inhibitors are effi cacious in several disease models, including inflammation, arthritis and ot her joint diseases, septic shock, and myocardial injury. In all cases, p38 activation in key cell types correlated with disease initiation and progres sion. Treatment with p38 MAP kinase inhibitors attenuated both p38 activati on and disease severity. Structurally diverse p38 MAP kinase inhibitors hav e been tested extensively in preclinical studies. (C) 2000 Elsevier Science B.V. All rights reserved.