1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

2011 ◽  
Vol 54 (22) ◽  
pp. 7899-7910 ◽  
Author(s):  
Wenceslao Lumeras ◽  
Laura Vidal ◽  
Bernat Vidal ◽  
Cristina Balagué ◽  
Adelina Orellana ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Selective Inhibitors ◽  
Mitogen Activated Protein

p38 Pathway Kinases as Anti-inflammatory Drug Targets

2007 ◽  
Vol 86 (9) ◽  
pp. 800-811 ◽  
Author(s):  
J.F. Schindler ◽  
J.B. Monahan ◽  
W.G. Smith
Keyword(s):  
Protein Kinase ◽  
Nuclear Export ◽  
Intracellular Signaling ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
Direct Proof ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Selective Inhibitors ◽  
Mitogen Activated Protein

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. p38α is a key MAPK involved in tumor necrosis factor α 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 p38α 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.

Specificity and mechanism of action of some commonly used protein kinase inhibitors

2000 ◽  
Vol 351 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Stephen P. DAVIES ◽  
Helen REDDY ◽  
Matilde CAIVANO ◽  
Philip COHEN
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Specific Protein ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Selective Inhibitors ◽  
Mitogen Activated Protein ◽  
Additional Protein

The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

Age-Related Changes in Activation of Mitogen-Activated Protein Kinase Cascades by Oxidative Stress

1998 ◽  
Vol 3 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Kathryn Z Guyton ◽  
Myriani Gorospe ◽  
Xiantao Wang ◽  
Yolanda D Mock ◽  
Gertrude C Kokkonen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Age Related ◽  
Mitogen Activated Protein ◽  
Age Related Changes
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