MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein

Abstract

Mitogen-activated protein kinase p38 is a serine/threonine kinase originally isolated from lipopolysaccharide (LPS) stimulated monocytes. There are four isoforms p38alpha p38beta, p38gamma, and p38delta. The most thoroughly studied isoform is p38alpha, whose activation has been observed in many hematopoietic and non-hematopoietic cell types upon appropriate stimuli. Subsequently, p38alpha kinase has been shown to be involved in the biosynthesis of TNFalpha and IL-1beta at the translational and transcriptional level. MAP kinase p38alpha represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. The discovery and publication of p38alpha and the pyridinyl-imidazole inhibitor initiated a huge effort by many companies to develop p38alpha inhibitors as potential treatment for inflammatory diseases. Herein we provide a brief overview of recent reported clinical results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO 323. However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature.

Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms

“…Several compounds are in trials targeting p38 MAPK also in cardiovascular diseases, such as acute coronary syndrome (ACS) and inflammatory cardiovascular disorders. For example, a p38 inhibitor SB618323 is developed for treatment of coronary heart disease, and another inhibitor VX-702 is being studied in the treatment of ACS (Lee and Dominguez, 2005;Ding, 2006). Our present results highlight that more information about differences between the distinct p38 isoforms is needed to determine whether the pharmacological manipulation of p38 is useful in the treatment of cardiovascular and other diseases.…”

Treatment with Histone Deacetylase Inhibitor Attenuates MAP Kinase Mediated Liver Injury in a Lethal Model of Septic Shock

“…P38 belongs to a family of serine/threonine protein kinases with four different isoforms, of which the α isoform is the most studied [ 19 ]. It was first discovered in Finkelstein et al Page 5 monocytes, where it was noted to be phosphorylated and activated by LPS [ 4 ]. In a positive feedback loop, p38 regulates expression of cytokines and is also activated in immune cells by cytokines [ 20 ].…”

“…Animal studies have demonstrated that p38 MAPK inhibitors improve survival in sepsis [ 7 -9 ]. In addition, p38 inhibitors have been shown to decrease TNF-α in human whole blood stimulated by LPS, and also decrease TNF-α stimulation of other inflammatory cytokines such as IL-1β and IL-6 [ 4 ].…”

Glycoprotein 120 Binding to CXCR4 Causes p38-Dependent Primary T Cell Death That Is Facilitated by, but Does Not Require Cell-Associated CD4

“…To study whether gp120-mediated p38 activation is a necessary event for gp120-induced CD4 T cell death, we used the specific p38 inhibitor, SB203580 (39). As shown in Fig.…”