Review
Inhibition of p38 MAP kinase as a therapeutic strategy

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Abstract

Since the discovery of p38 MAP kinase in 1994, our understanding of its biology has progressed dramatically. The key advances include (1) identification of p38 MAP kinase homologs and protein kinases that act upstream and downstream from p38 MAP kinase, (2) identification of interesting and potentially 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 differ in their tissue distribution, regulation of kinase activation and subsequent phosphorylation of downstream substrates. They also differ in terms of their sensitivities toward the p38 MAP kinase inhibitors. The best-studied isoform is p38 alpha, whose activation has been observed in many hematopoietic and non-hematopoietic cell types upon treatment with appropriate stimuli. The pyridinylimidazole compounds, exemplified by SB 203580, were originally prepared as inflammatory cytokine synthesis inhibitors that subsequently were found to be selective inhibitors of p38 MAP kinase. SB 203580 inhibits the catalytic activity of p38 MAP kinase by competitive binding in the ATP pocket. X-ray crystallographic studies of the target enzyme complexed with inhibitor reinforce the observations made from site-directed mutagenesis studies, thereby providing a molecular basis for understanding the kinase selectivity of these inhibitors. The p38 MAP kinase inhibitors are efficacious in several disease models, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury. In all cases, p38 activation in key cell types correlated with disease initiation and progression. Treatment with p38 MAP kinase inhibitors attenuated both p38 activation and disease severity. Structurally diverse p38 MAP kinase inhibitors have been tested extensively in preclinical studies.

Section snippets

p38 MAP kinase homologs

As is the case with both ERKs and JNKs, multiple members of the p38 MAP kinase family have been identified (Cobb and Goldsmith, 1995). Murine p38 was first identified as a kinase activated in response to bacterial LPS (Han et al., 1994). Soon after, human CSBP1 and CSBP2/p38 were identified as targets of a class of pyridinylimidazole compounds that inhibited the production of inflammatory cytokines from activated monocyte/macrophages (Lee et al., 1994). CSBP1 and CSBP2 differ from each other by

Substrates

A number of substrates of p38 MAP kinase have been identified. These include other kinases such as MAPKAP K2/3, p38-regulated/activated protein kinase (PRAK), MAP kinase-interacting kinase 1 and 2 (MNK1/2), mitogen and stress-activated kinase 1 (MSK1)/RLPK, and ribosomal S6 kinase-B (RSK-B); transcription factors such as activation transcription factors 2 and 6 (ATF2/6), myocyte enhancer factor 2C (MEF2C), C/EBP homologous protein (CHOP), Elk1 and SAP-1A and cytosolic proteins such as stathmin.

Signaling pathways involving p38 MAP kinase

Significant progress has been made in defining the exact molecular pathways of p38 MAP kinase activation and subsequent signaling. Members of the p38 MAP kinase family are phosphorylated on Thr and Tyr residues in a Thr-Gly-Tyr motif by a dual specificity MKK. Initially, it was thought that among upstream MKKs, MKK 3, 4 and 6 all activated p38 MAP kinase Derijard et al., 1995, Han et al., 1996, Raingeaud et al., 1996. However, recent data suggest that MKK6 and, under certain conditions, MKK3

Role of p38 MAP kinase in cytokine production and function

The role of p38 MAP kinase in the regulation of cytokine production or function was not appreciated until the discovery of p38 MAP kinase activation in LPS stimulated macrophages (Han et al., 1994) and the simultaneous identification of the molecular target of compounds previously shown to inhibit cytokine biosynthesis (Lee et al., 1994). It is now known that the regulation of cytokine biosynthesis in many different cell types is regulated through activation of p38 MAP kinase Beyaert et al.,

p38 MAP kinase and hematopoietic cells

In murine T-cells, the p38 MAP kinase inhibitor, SB 203580 inhibited the production of interferon-gamma by Th1 cells without affecting IL-4 production by Th2 cells (Rincon et al., 1998). Overexpression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses whereas constitutively activated MKK6 overexpression caused increased production of interferon-gamma. In another study, it was shown that SB 203580 inhibited CD28-dependent T-cell proliferation and IL-2 in vitro

Inflammatory diseases

The widely used p38 MAP kinase inhibitor, SB 203580, has been profiled in a number of models in vivo and demonstrated its activity in a wide variety of TNF alpha mediated disease models (Badger et al., 1996). The compound inhibited LPS-induced TNF production with IC50 of 15 and 25 mg/kg in mice and rats, respectively. It was effective in reducing paw inflammation in the adjuvant arthritic rat with optimum inhibition observed at 60 mg/kg. There is also evidence for protection of joint integrity

Compounds

The bicylic pyridinylimidazole SKF 86002 was first reported to inhibit LPS-stimulated cytokine production Lee et al., 1988, Lee et al., 1993, Lee et al., 1994, Lee et al., 1999. In 1993, the SAR for inhibition of cytokine synthesis by bicyclic imidazoles was described in a publication which explored dual 5-LO/COX and cytokine inhibition as potential mechanisms for the potent anti-inflammatory activity of these compounds (Lee et al., 1993). Subsequently, SB 203580, and other 2,4,5-triaryl

Conclusion and perspectives

Our increased understanding of the signal transduction pathways involved in the regulation of cytokine production and cytokine signaling in immune cells has opened the door for the discovery of novel therapeutics useful in treating a variety of inflammatory diseases in which cytokine production or signaling is implicated. The availability of potent and selective inhibitors of such signaling pathways also provide a means to further dissect the pathways to increase our understanding of the

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