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Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38\u03b1 is a key MAPK involved in tumor necrosis factor \u03b1 and other cytokine production, as well as enzyme induction (cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinases) and adhesion molecule expression. An understanding of the broad biologic and pathophysiological roles of p38 MAPK family members has grown significantly over the past decade, as has the complexity of the signaling network leading to their activation. Downstream substrates of MAPK include other kinases ( e.g., mitogen-activated protein-kinase-activated protein kinase 2) and factors that regulate transcription, nuclear export, and mRNA stability and translation. The high-resolution crystal structure of p38\u03b1 has led to the design of selective inhibitors that have good pharmacological activity. Despite the strong rationale for MAPK inhibitors in human disease, direct proof of concept in the clinic has yet to be demonstrated, with most compounds demonstrating dose-limiting adverse effects. The role of MAPK in inflammation makes them attractive targets for new therapies, and efforts are continuing to identify newer, more selective inhibitors for inflammatory diseases.<\/jats:p>","DOI":"10.1177\/154405910708600902","type":"journal-article","created":{"date-parts":[[2009,1,8]],"date-time":"2009-01-08T19:39:42Z","timestamp":1231443582000},"page":"800-811","source":"Crossref","is-referenced-by-count":201,"title":["p38 Pathway Kinases as Anti-inflammatory Drug Targets"],"prefix":"10.1177","volume":"86","author":[{"given":"J.F.","family":"Schindler","sequence":"first","affiliation":[{"name":"Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.B.","family":"Monahan","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.G.","family":"Smith","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2007,9,1]]},"reference":[{"key":"ADAMS-ETAL-2001","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6468(08)70091-2"},{"key":"AGUIRRE-GHISO-ETAL-2003","doi-asserted-by":"crossref","unstructured":"Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003). 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