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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 20; pp. 7275 - 7280
• Main Authors: Hellmuth, Klaus, Grosskopf, Stefanie, Lum, Ching Tung, Würtele, Martin, Röder, Nadine, von Kries, Jens Peter, Rosario, Marta, Rademann, Jörg, Birchmeier, Walter
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.05.2008; National Acad Sciences
• Subjects: active sites; Adenosine triphosphatase; Animals; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Biological Sciences; Cancer; Catalytic Domain; Cell growth; Cells; dephosphorylation; Dogs; Drug Screening Assays, Antitumor; Epithelial cells; Gene Expression Regulation; HEK293 cells; hepatocyte growth factor; Hepatocyte Growth Factor - metabolism; Hepatocytes; Humans; Hydrazones - chemistry; Hydrazones - pharmacology; Kinases; Kinetics; Leukemia; Leukemia - metabolism; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Models, Biological; Molecular weight; morphogenesis; mutants; Mutation; neoplasm cells; oncogenes; Phosphatases; phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - physiology; protein-tyrosine-phosphatase; Proteins; Pyrazolones - chemistry; Receptors; Signal transduction; Structure-Activity Relationship; therapeutics; Tumor cell line; tyrosine
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0710468105

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.