Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1.
Protein tyrosine phosphatases have a central role in the maintenance of normal cellular functionality. For example, PTP1B has been implicated in insulin-resistance, obesity, and neoplasia. Mitogen-activated protein kinase phosphatase-1 (MKP-1 or DUSP1) dephosphorylates and inactivates mitogen-activated protein kinase (MAPK) substrates, such as p38, JNK, and Erk, and has been implicated in neoplasia. The lack of readily available selective small molecule inhibitors of MKP family members has severely limited interrogation of their biological role. Inspired by a previously identified inhibitor (NSC 357756) of MKP-3, we synthesized seven NSC 357756 congeners, which were evaluated for in vitro inhibition against several protein phosphatases. Remarkably, none displayed potent inhibition against MKP-3, including the desamino NSC 357756 analog NU-154. Interestingly, NU-154 inhibited human PTP1B in vitro with an IC(50) value of 24 +/- 1 microM and showed little inhibition against Cdc25B, MKP-1, and VHR phosphatases. NU-126 [2-((E)-2-(5-cyanobenzofuran-2-yl)vinyl)-1H-indole-6-carbonitrile] inhibited MKP-1 and VHR in vitro but was less active against human MKP-3, Cdc25B, and PTP1B. The inhibition of MKP-1 by NU-126 was independent of redox processes. The benzofuran substructure represents a new potential scaffold for further analog development and provides encouragement that more selective and potent inhibitors of MKP family members may be achievable.
Lazo
John S
JS
The University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, PA 15261, USA. lazo@pitt.edu
Nunes
Ruth
R
Skoko
John J
JJ
Queiroz de Oliveira
Pierre E
PE
Vogt
Andreas
A
Wipf
Peter
P
D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D054640:Dual Specificity Phosphatase 3; D054642:Dual Specificity Phosphatase 6; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity; D020687:cdc25 Phosphatases / Q000378:metabolism
D001572:Benzofurans; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; C483753:NSC 357756; D019950:Mitogen-Activated Protein Kinase 1; D054645:Protein Phosphatase 1; C517008:CDC25B protein, human; C517025:DUSP3 protein, human; C517035:DUSP6 protein, human; D054640:Dual Specificity Phosphatase 3; D054642:Dual Specificity Phosphatase 6; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases; C105430:benzofuran