Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking.
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.
Hellmuth
Klaus
K
Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, D-13125 Berlin, Germany.
Grosskopf
Stefanie
S
Lum
Ching Tung
CT
Würtele
Martin
M
Röder
Nadine
N
von Kries
Jens Peter
JP
Rosario
Marta
M
Rademann
Jörg
J
Birchmeier
Walter
W
D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D007938:Leukemia / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism / Q000502:physiology*; D047069:Pyrazolones / Q000737:chemistry; D013329:Structure-Activity Relationship
D001557:Benzenesulfonates; D006835:Hydrazones; D047069:Pyrazolones; C529675:phenylhydrazonopyrazolone sulfonate 1; C038362:pyrazolone; D017228:Hepatocyte Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11