Synthesis and biological activity of a focused library of mitogen-activated protein kinase phosphatase inhibitors.
Mitogen-activated protein kinase phosphatase 1 is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates mitogen-activated protein kinase substrates, such as p38, c-Jun-N-terminal kinase, and extracellular signal-related kinase. These mitogen-activated protein kinase substrates regulate many cellular processes associated with human diseases. In spite of this potential as a molecular target for chemotherapy, however, pharmacologically tractable inhibitors of mitogen-activated protein kinase phosphatase-1 have yet to be developed. Based on the results from a high-throughput screen for small molecule inhibitors of mitogen-activated protein kinase phosphatase-1, we designed, synthesized, and evaluated a focused library in an effort to further understand the structural requirements for mitogen-activated protein kinase phosphatase-1 inhibitory activity.
Arnold
David M
DM
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Foster
Caleb
C
Huryn
Donna M
DM
Lazo
John S
JS
Johnston
Paul A
PA
Wipf
Peter
P
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019151:Peptide Library; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases