MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein.
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.
Lee
Matthew R
MR
Department of Molecular Structure, Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799, USA. mrlee@amgen.com
Dominguez
Celia
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D048308:Mitogen-Activated Protein Kinase 14