MAP Kinase Structure
Published by Anonymous on 2007/9/28 (2063 reads)
1: Mini Rev Med Chem. 2005 Sep;5(9):857-68.
Structure-activity relationships of p38 mitogen-activated protein kinase inhibitors.
Bolós J.
Prous Institute for Collaborative Biomedical Research; Barcelona Science Park, Laboratory P1C41, 08028 Barcelona, Spain. JORDI-BOLOS@terra.es
Rheumatoid arthritis and other chronic inflammatory diseases constitute a major therapeutic challenge, usually not sufficiently met by the classical antiinflammatory medications. Recent research efforts provided new insights into the molecular basis of these pathologies and disclosed new opportunities for developing improved drugs directed to the chemical mediators of the disease. The enzyme p38 MAP kinase plays a central role in the signal transduction cascade that leads to the production of both the proinflammatory cytokines, TNF-alpha and IL-1 beta, thus representing an attractive therapeutic target for novel antiinflammatory therapies. A number of p38 inhibitors belonging to different structural families have been developed as potential antiinflammatory drugs, and some of them progressed into clinical trials. The initial pyridinyl imidazole inhibitors contributed to the identification and characterization of p38 MAP kinase as the molecular target of these new drugs, and were found to act as competitive inhibitors at the ATP binding site of the enzyme. A number of variations in the pyridine and imidazole rings were subsequently introduced. Other inhibitors structurally unrelated to the pyridinylimidazoles have also been developed, such as the pyridopyridazinones, diaryl ureas, aminobenzophenones and aromatic amides. One of these structural classes, the N,N'-diarylureas, has been found to interact with a distinct allosteric site of p38 MAP kinase and requires a deep conformational change prior to binding.
Publication Types:
Review
PMID: 16178727 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Pharmacol Ther. 1999 May-Jun;82(2-3):399-407.
Peptide inhibitors of the mitogen-activated protein kinase pathway: a structure -mimetic peptide corresponding to the conserved inter-DFG-APE region in the kinase domain.
Fukami Y, Tokmakov AA, Konaka K, Sato K.
Biosignal Research Center and Graduate School of Science and Technology, Kobe University, Nada, Japan.
The signal transduction pathway mediated by mitogen-activated protein kinases is an attractive target for the design of pharmacologically effective inhibitors. Two specific cell-permeant small molecule inhibitors of this pathway have been reported. However, under certain circumstances, nonpermeable inhibitors, such as neutralizing antibodies and peptide inhibitors, are also useful. We present here a novel approach for such peptide inhibitor design. The procedure is based on the synthesis of a structure-mimetic peptide corresponding to a short peptide segment in the target molecule. The results obtained so far show that a peptide designed in such a way is an effective inhibitor of the pathway. The possible application of such peptides and antipeptide antibodies as probes for protein kinase regulation mechanisms is also evaluated.
Publication Types:
Review
PMID: 10454215 [PubMed - indexed for MEDLINE]
Structure-activity relationships of p38 mitogen-activated protein kinase inhibitors.
Bolós J.
Prous Institute for Collaborative Biomedical Research; Barcelona Science Park, Laboratory P1C41, 08028 Barcelona, Spain. JORDI-BOLOS@terra.es
Rheumatoid arthritis and other chronic inflammatory diseases constitute a major therapeutic challenge, usually not sufficiently met by the classical antiinflammatory medications. Recent research efforts provided new insights into the molecular basis of these pathologies and disclosed new opportunities for developing improved drugs directed to the chemical mediators of the disease. The enzyme p38 MAP kinase plays a central role in the signal transduction cascade that leads to the production of both the proinflammatory cytokines, TNF-alpha and IL-1 beta, thus representing an attractive therapeutic target for novel antiinflammatory therapies. A number of p38 inhibitors belonging to different structural families have been developed as potential antiinflammatory drugs, and some of them progressed into clinical trials. The initial pyridinyl imidazole inhibitors contributed to the identification and characterization of p38 MAP kinase as the molecular target of these new drugs, and were found to act as competitive inhibitors at the ATP binding site of the enzyme. A number of variations in the pyridine and imidazole rings were subsequently introduced. Other inhibitors structurally unrelated to the pyridinylimidazoles have also been developed, such as the pyridopyridazinones, diaryl ureas, aminobenzophenones and aromatic amides. One of these structural classes, the N,N'-diarylureas, has been found to interact with a distinct allosteric site of p38 MAP kinase and requires a deep conformational change prior to binding.
Publication Types:
Review
PMID: 16178727 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Pharmacol Ther. 1999 May-Jun;82(2-3):399-407.
Peptide inhibitors of the mitogen-activated protein kinase pathway: a structure -mimetic peptide corresponding to the conserved inter-DFG-APE region in the kinase domain.
Fukami Y, Tokmakov AA, Konaka K, Sato K.
Biosignal Research Center and Graduate School of Science and Technology, Kobe University, Nada, Japan.
The signal transduction pathway mediated by mitogen-activated protein kinases is an attractive target for the design of pharmacologically effective inhibitors. Two specific cell-permeant small molecule inhibitors of this pathway have been reported. However, under certain circumstances, nonpermeable inhibitors, such as neutralizing antibodies and peptide inhibitors, are also useful. We present here a novel approach for such peptide inhibitor design. The procedure is based on the synthesis of a structure-mimetic peptide corresponding to a short peptide segment in the target molecule. The results obtained so far show that a peptide designed in such a way is an effective inhibitor of the pathway. The possible application of such peptides and antipeptide antibodies as probes for protein kinase regulation mechanisms is also evaluated.
Publication Types:
Review
PMID: 10454215 [PubMed - indexed for MEDLINE]
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