Discovery of a novel Shp2 protein tyrosine phosphatase inhibitor

Liwei Chen, Shen Shu Sung, M. L.Richard Yip, Harshani R. Lawrence, Yuan Ren, Wayne C. Guida, Said M. Sebti, Nicholas J. Lawrence, Jie Wu

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

Shp2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. It is involved in growth factor-induced activation of mitogen-activated protein (MAP) kinases Erk1 and Erk2 (Erk1/2) and has been implicated in the pathogenicity of the oncogenic bacterium Helicobacter pylori. Moreover, gain-of-function Shp2 mutations have been found in childhood leukemias and Noonan syndrome. Thus, small molecule Shp2 PTP inhibitors are much needed reagents for evaluation of Shp2 as a therapeutic target and for chemical biology studies of Shp2 function. By screening the National Cancer Institute (NCI) Diversity Set chemical library, we identified 8-hydroxy-7-(6-sulfonaphthalen-2- yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877) as a potent Shp2 PTP inhibitor. Molecular modeling and site-directed mutagenesis studies suggested that NSC-87877 binds to the catalytic cleft of Shp2 PTP. NSC-87877 cross-inhibited Shp1 in vitro, but it was selective for Shp2 over other PTPs (PTP1B, HePTP, DEP1, CD45, and LAR). It is noteworthy that NSC-87877 inhibited epidermal growth factor (EGF)-induced activation of Shp2 PTP, Ras, and Erk1/2 in cell cultures but did not block EGF-induced Gab1 tyrosine phosphorylation or Gab1-Shp2 association. Furthermore, NSC-87877 inhibited Erk1/2 activation by a Gab1-Shp2 chimera but did not affect the Shp2-independent Erk1/2 activation by phorbol 12-myristate 13-acetate. These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. Our study also provides the first pharmacological evidence that Shp2 mediates EGF-induced Erk1/2 MAP kinase activation.

Original languageEnglish (US)
Pages (from-to)562-570
Number of pages9
JournalMolecular pharmacology
Volume70
Issue number2
DOIs
StatePublished - 2006

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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    Chen, L., Sung, S. S., Yip, M. L. R., Lawrence, H. R., Ren, Y., Guida, W. C., Sebti, S. M., Lawrence, N. J., & Wu, J. (2006). Discovery of a novel Shp2 protein tyrosine phosphatase inhibitor. Molecular pharmacology, 70(2), 562-570. https://doi.org/10.1124/mol.106.025536