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

doi:10.1073/pnas.0710468105

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

*Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, D-13125 Berlin, Germany;
^†Leibniz Institute for Molecular Pharmacology, Robert Rössle Strasse 10, D-13125 Berlin, Germany; and
^¶Institute for Chemistry and Biochemistry, Free University Berlin, Takustrasse 3, D-14195 Berlin, Germany

Edited by Axel Ullrich, Max Planck Institute, Martinsried, Germany, and accepted by the Editorial Board February 20, 2008 (received for review November 2, 2007)

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: wbirch{at}mdc-berlin.de
Author contributions: K.H., J.P.v.K., and W.B. designed research; K.H., C.T.L., M.W., and N.R. performed research; S.G. and J.R. contributed new reagents/analytic tools; K.H. and W.B. analyzed data; and K.H., M.R., and W.B. wrote the paper.
↵ ^‡Present address: Department of Biophysics, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu 862, 04023-062, São Paulo, Brazil.
↵ ^§Present address: Silence Therapeutics AG, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. A.U. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710468105/DCSupplemental.