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Inhibitors of Protein Kinases and Protein Phosphates pp 65–83Cite as

Pharmacological Potential of p38 MAPK Inhibitors

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 167))

Abstract

A key component of the intracellular signaling pathways involved in cellular response to environmental stress and inflammatory cytokines is the p38 family of mitogen-activated protein kinases (MAPKs). Of the four isoforms of the p38 family of MAPKs identified thus far, p38α is the most characterized enzyme. Since the discovery of p38α MAPK as a target of a series of compounds that inhibited the production of inflammatory cytokines, an intense effort has been applied to further identify, develop, and refine highly potent and selective inhibitors of this enzyme. In addition, availability of p38α MAPK inhibitors has allowed the investigators to dissect this signaling pathway and to examine its role in various pathologies. A large body of biochemical as well as genetic evidence indicates a critical role of p38α MAPK in both the production of inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF) and subsequent signaling initiated in response to these cytokines. This suggests that inhibition of p38α MAPK pathway will have utility in pathological settings where tissue inflammation and pro-inflammatory cytokines have been implicated. Indeed, several p38α MAPK inhibitors have been shown to be efficacious in preclinical animal models of a variety of diseases, including rheumatoid arthritis, pulmonary diseases, neuronal protection, and cancer. In the past few years, several groups have advanced inhibitors into early clinical studies for rheumatoid arthritis, but none thus far has reached the critical phase III efficacy stage. In this chapter, we review the p38 MAPK pathway and pharmacological potential of p38α MAPK inhibitors in various pathologies with particular emphasis on inflammatory diseases.

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  1. GlaxoSmithKline, UP1340, 1250 South Collegeville Rd., P.O. Box 5089, Collegeville, PA, 19426-0989, USA

    S. Kumar & S. M. Blake

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  1. S. Kumar
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Editors and Affiliations

  1. Dipartimento di Chimica Biologica, Università di Padova, Via Trieste 75, Padova, 35121, Italy

    Lorenzo A. Pinna

  2. MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow St., Dundee, DD1 5EH, Scotland, UK

    Patricia T.W. Cohen Ph.D. (Professor of Molecular Biology) (Professor of Molecular Biology)

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Kumar, S., Blake, S.M. (2005). Pharmacological Potential of p38 MAPK Inhibitors. In: Pinna, L.A., Cohen, P.T. (eds) Inhibitors of Protein Kinases and Protein Phosphates. Handbook of Experimental Pharmacology, vol 167. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26670-4_4

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