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Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

[ Vol. 6 , Issue. 6 ]


C. J. Malemud   Pages 689 - 698 ( 10 )


The stress-activated protein kinase (SAPK) and mitogen-activated protein kinase (MAPK) subfamilies are crucial to environmental stress responses and responses to growth factors that cause transcriptional activation of genes required for cell proliferation, differentiation and programmed cell death. Small molecular compounds with specific structure/activity characteristics have been developed that competitively block SAPK/MAPK binding to ATP. Chemically modified compounds based on ATP binding pocket characteristics have improved selectivity and specificity for SAPK/MAPK isoforms. In addition, sitespecific mutagenesis of MAPKs has helped identify the MAPK structures required for binding recognition and selectivity of these inhibitors. A group of extracellular-signal regulated protein kinase (ERK) inhibitors has been constructed based almost exclusively on their ability to inhibit the ERK activation cascade. Inhibitors have been employed in vitro to identify protein targets and mechanism of action of SAPKs/MAPKs. The efficacy of SAPK/MAPK inhibitors in animal models of inflammation, arthritis, heart failure, cancer and neurological degeneration has provided the impetus for using them in human studies of inflammation and in clinical trials.


Stress-activated protein kinase, mitogen-activated protein kinase, c-jun-N-amino-terminal kinase, p38 kinase, extracellular signal-regulated kinase, anthrapyrazolone, pyridinyl imidazole, methoxyflavone


Division of RheumaticDiseases/Department of Medicine and Department of Anatomy, CaseWestern Reserve University School of Medicine and University Hospitalsof Cleveland, Cleveland, Ohio 44106-5076, USA.

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