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

TitleSpecific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking
Authors
Issue Date2008
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2008, v. 105 n. 20, p. 7275-7280 How to Cite?
AbstractThe 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. © 2008 by The National Academy of Sciences of the USA.
Persistent Identifierhttp://hdl.handle.net/10722/168304
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHellmuth, Ken_US
dc.contributor.authorGrosskopf, Sen_US
dc.contributor.authorChing, TLen_US
dc.contributor.authorWürtele, Men_US
dc.contributor.authorRöder, Nen_US
dc.contributor.authorVon Kries, JPen_US
dc.contributor.authorRosario, Men_US
dc.contributor.authorRademann, Jen_US
dc.contributor.authorBirchmeier, Wen_US
dc.date.accessioned2012-10-08T03:17:17Z-
dc.date.available2012-10-08T03:17:17Z-
dc.date.issued2008en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2008, v. 105 n. 20, p. 7275-7280en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/168304-
dc.description.abstractThe 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. © 2008 by The National Academy of Sciences of the USA.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBenzenesulfonates - Chemistry - Pharmacologyen_US
dc.subject.meshCatalytic Domainen_US
dc.subject.meshDogsen_US
dc.subject.meshDrug Screening Assays, Antitumoren_US
dc.subject.meshGene Expression Regulationen_US
dc.subject.meshHepatocyte Growth Factor - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshHydrazones - Chemistry - Pharmacologyen_US
dc.subject.meshKineticsen_US
dc.subject.meshLeukemia - Metabolismen_US
dc.subject.meshMitogen-Activated Protein Kinase 1 - Metabolismen_US
dc.subject.meshMitogen-Activated Protein Kinase 3 - Metabolismen_US
dc.subject.meshModels, Biologicalen_US
dc.subject.meshProtein Tyrosine Phosphatase, Non-Receptor Type 11 - Metabolism - Physiologyen_US
dc.subject.meshPyrazolones - Chemistryen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.titleSpecific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput dockingen_US
dc.typeArticleen_US
dc.identifier.emailChing, TL:ctlum@graduate.hku.hken_US
dc.identifier.authorityChing, TL=rp00757en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1073/pnas.0710468105en_US
dc.identifier.pmid18480264-
dc.identifier.scopuseid_2-s2.0-44449083477en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-44449083477&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume105en_US
dc.identifier.issue20en_US
dc.identifier.spage7275en_US
dc.identifier.epage7280en_US
dc.identifier.isiWOS:000256162900032-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHellmuth, K=36885947800en_US
dc.identifier.scopusauthoridGrosskopf, S=24334473200en_US
dc.identifier.scopusauthoridChing, TL=7006889374en_US
dc.identifier.scopusauthoridWürtele, M=7003512133en_US
dc.identifier.scopusauthoridRöder, N=24336100600en_US
dc.identifier.scopusauthoridVon Kries, JP=6603183899en_US
dc.identifier.scopusauthoridRosario, M=7005511200en_US
dc.identifier.scopusauthoridRademann, J=7004141460en_US
dc.identifier.scopusauthoridBirchmeier, W=7005741430en_US

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