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p38 Pathway Kinases as Anti-inflammatory Drug Targets

Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA

^* corresponding author, walter.g.smith{at}pfizer.com

Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules involved in cytokine synthesis. Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38 is a key MAPK involved in tumor necrosis factor 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 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.

KEY WORDS: mitogen-activated protein kinases • p38 • rheumatoid arthritis • Crohn’s disease • inflammation • drug discovery • MAPKAP kinase • intracellular signaling

Abbreviations: MAPK, mitogen-activated protein kinase • ERK, extracellular signaling kinase • JNK, c-jun N-terminal kinase • COX2, cyclo-oxygenase-2 • iNOS, inducible nitric oxide synthase • MMP, matrix metalloproteinase • MAPKK, mitogen-activated protein kinase kinase • MK-2, mitogen-activated protein-kinase-activated protein kinase-2 • MAPKAP, mitogen-activated protein kinase-activated protein • MAPKKK, mitogen-activated protein kinase kinase kinase • RANKL, receptor activator of NF-B ligand • MNK, MAP kinase signal-integrating kinase • MSK, mitogen and stress-activated protein kinase • RSK, ribosomal S6 kinase • AP-1, activator protein-1 • Tpl, tumor progression locus 2 • IL, interleukin • ASK1, apoptosis signal-regulating kinase 1 • TAO, thousand-and-one amino acids • MLK3, mixed-lineage kinase 3 • TBK, transforming growth factor ß activated protein kinase • TGFß, transforming growth factor ß • LPS, lipopolysaccharide • TRAF6, TNF receptor-associated factor 6 • MKK, mitogen-activated protein kinase kinase • TAK-1, TGF-beta activated protein kinase • GRK2, G-protein coupled receptor kinase-2 MKPs, MAP kinase phosphatases • PRAK, p38 regulated/activated protein kinase • IFN, interferon gamma • AREs, AU-rich elements • AUBPs, AU-rich binding proteins • TTP, tristetraprolin • hnRNP A0, heterogeneous nuclear ribonuclear protein A0 • HUR, human R antigen • PGE₂, prostaglandin E₂ • Hsp27, small heat-shock protein-27 • TNF-, tumor necrosis factor alpha

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