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Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1

Lazo, JS and Nunes, R and Skoko, JJ and de Oliveira, PEQ and Vogt, A and Wipf, P (2006) Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1. Bioorganic and Medicinal Chemistry, 14 (16). 5643 - 5650. ISSN 0968-0896

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Abstract

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 IC50 value of 24 ± 1 μM 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. © 2006 Elsevier Ltd. All rights reserved.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lazo, JSlazo@pitt.eduLAZO
Nunes, R
Skoko, JJ
de Oliveira, PEQ
Vogt, A
Wipf, Ppwipf@pitt.eduPWIPF
Date: 15 August 2006
Date Type: Publication
Journal or Publication Title: Bioorganic and Medicinal Chemistry
Volume: 14
Number: 16
Page Range: 5643 - 5650
DOI or Unique Handle: 10.1016/j.bmc.2006.04.036
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0968-0896
MeSH Headings: Benzofurans--chemical synthesis; Benzofurans--pharmacology; Cell Cycle Proteins--metabolism; Dual Specificity Phosphatase 3; Dual Specificity Phosphatase 6; Enzyme Activation; Enzyme Inhibitors--chemical synthesis; Enzyme Inhibitors--pharmacology; Humans; Imidazoles--pharmacology; Inhibitory Concentration 50; Kinetics; Mitogen-Activated Protein Kinase 1--antagonists & inhibitors; Phosphorylation; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases--antagonists & inhibitors; Protein Tyrosine Phosphatases--metabolism; Substrate Specificity; cdc25 Phosphatases--metabolism
PubMed ID: 16698271
Date Deposited: 30 Oct 2013 16:58
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/19901

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