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Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Item Type:Article
Title:Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking
Creators Name:Hellmuth, K. and Grosskopf, S. and Lum, C.T. and Wuertele, M. and Roeder, N. and von Kries, J.P. and Rosario, M. and Rademann, J. and Birchmeier, W.
Abstract:The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cell-permeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases.
Keywords:Chemical Biology, Growth Factor Signaling, Phosphatase Inhibition, Virtual Drug Screening, Animals, Dogs
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:105
Number:20
Page Range:7275-7280
Date:20 May 2008
Official Publication:https://doi.org/10.1073/pnas.0710468105
PubMed:View item in PubMed

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