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

被引：189

作者：

Hellmuth, Klaus ^{[1
]}

Grosskopf, Stefanie ^{[2
]}

Lum, Ching Tung ^{[1
]}

Wuertele, Martin ^{[1
]}

Roeder, Nadine ^{[1
]}

von Kries, Jens Peter ^{[2
]}

Rosario, Marta ^{[1
]}

Rademann, Joerg ^{[2
,3
]}

Birchmeier, Walter ^{[1
]}

机构：

[1] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany

[2] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany

[3] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 20期

关键词：

chemical biology; growth factor signaling; phosphatase inhibition; virtual drug screening;

D O I：

10.1073/pnas.0710468105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. PHIPS1 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.

引用

页码：7275 / 7280

页数：6

共 58 条

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