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- Publisher Website: 10.1073/pnas.0710468105
- Scopus: eid_2-s2.0-44449083477
- PMID: 18480264
- WOS: WOS:000256162900032
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Article: Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking
Title | Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking |
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Authors | |
Keywords | Chemical biology Growth factor signaling Phosphatase inhibition Virtual drug screening |
Issue Date | 2008 |
Publisher | National 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? |
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. © 2008 by The National Academy of Sciences of the USA. |
Persistent Identifier | http://hdl.handle.net/10722/168304 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Hellmuth, K | en_US |
dc.contributor.author | Grosskopf, S | en_US |
dc.contributor.author | Ching, TL | en_US |
dc.contributor.author | Würtele, M | en_US |
dc.contributor.author | Röder, N | en_US |
dc.contributor.author | Von Kries, JP | en_US |
dc.contributor.author | Rosario, M | en_US |
dc.contributor.author | Rademann, J | en_US |
dc.contributor.author | Birchmeier, W | en_US |
dc.date.accessioned | 2012-10-08T03:17:17Z | - |
dc.date.available | 2012-10-08T03:17:17Z | - |
dc.date.issued | 2008 | en_US |
dc.identifier.citation | Proceedings Of The National Academy Of Sciences Of The United States Of America, 2008, v. 105 n. 20, p. 7275-7280 | en_US |
dc.identifier.issn | 0027-8424 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/168304 | - |
dc.description.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. © 2008 by The National Academy of Sciences of the USA. | en_US |
dc.language | eng | en_US |
dc.publisher | National Academy of Sciences. The Journal's web site is located at http://www.pnas.org | en_US |
dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | en_US |
dc.subject | Chemical biology | - |
dc.subject | Growth factor signaling | - |
dc.subject | Phosphatase inhibition | - |
dc.subject | Virtual drug screening | - |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Benzenesulfonates - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Catalytic Domain | en_US |
dc.subject.mesh | Dogs | en_US |
dc.subject.mesh | Drug Screening Assays, Antitumor | en_US |
dc.subject.mesh | Gene Expression Regulation | en_US |
dc.subject.mesh | Hepatocyte Growth Factor - Metabolism | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Hydrazones - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Kinetics | en_US |
dc.subject.mesh | Leukemia - Metabolism | en_US |
dc.subject.mesh | Mitogen-Activated Protein Kinase 1 - Metabolism | en_US |
dc.subject.mesh | Mitogen-Activated Protein Kinase 3 - Metabolism | en_US |
dc.subject.mesh | Models, Biological | en_US |
dc.subject.mesh | Protein Tyrosine Phosphatase, Non-Receptor Type 11 - Metabolism - Physiology | en_US |
dc.subject.mesh | Pyrazolones - Chemistry | en_US |
dc.subject.mesh | Structure-Activity Relationship | en_US |
dc.title | Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking | en_US |
dc.type | Article | en_US |
dc.identifier.email | Ching, TL:ctlum@graduate.hku.hk | en_US |
dc.identifier.authority | Ching, TL=rp00757 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1073/pnas.0710468105 | en_US |
dc.identifier.pmid | 18480264 | - |
dc.identifier.scopus | eid_2-s2.0-44449083477 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-44449083477&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 105 | en_US |
dc.identifier.issue | 20 | en_US |
dc.identifier.spage | 7275 | en_US |
dc.identifier.epage | 7280 | en_US |
dc.identifier.isi | WOS:000256162900032 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Hellmuth, K=36885947800 | en_US |
dc.identifier.scopusauthorid | Grosskopf, S=24334473200 | en_US |
dc.identifier.scopusauthorid | Ching, TL=7006889374 | en_US |
dc.identifier.scopusauthorid | Würtele, M=7003512133 | en_US |
dc.identifier.scopusauthorid | Röder, N=24336100600 | en_US |
dc.identifier.scopusauthorid | Von Kries, JP=6603183899 | en_US |
dc.identifier.scopusauthorid | Rosario, M=7005511200 | en_US |
dc.identifier.scopusauthorid | Rademann, J=7004141460 | en_US |
dc.identifier.scopusauthorid | Birchmeier, W=7005741430 | en_US |
dc.identifier.issnl | 0027-8424 | - |