Hellmuth Klaus, Grosskopf Stefanie, Lum Ching Tung, Würtele Martin, Röder Nadine, von Kries Jens Peter, Rosario Marta, Rademann Jörg, Birchmeier Walter
Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, D-13125 Berlin, Germany.
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7275-80. doi: 10.1073/pnas.0710468105. Epub 2008 May 14.
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.
蛋白酪氨酸磷酸酶Shp2是生长因子信号传导的正向调节因子。多种白血病中的功能获得性突变将Shp2定义为一种真正的癌基因。我们对结合Shp2催化位点的小分子化合物进行了高通量计算机筛选。我们已鉴定出苯腙基吡唑啉酮磺酸盐PHPS1是一种强效且可透过细胞的抑制剂，它对Shp2具有特异性，而对密切相关的酪氨酸磷酸酶Shp1和PTP1B则不然。PHPS1抑制依赖Shp2的细胞事件，如肝细胞生长因子/分散因子（HGF/SF）诱导的上皮细胞分散和分支形态发生。PHPS1还阻断依赖Shp2的下游信号传导，即HGF/SF诱导的Erk1/2丝裂原活化蛋白激酶的持续磷酸化和桩蛋白的去磷酸化。此外，PHPS1有效抑制白血病相关的Shp2突变体Shp2-E76K对Erk1/2的激活，并阻断多种人类肿瘤细胞系的非锚定依赖性生长。因此，PHPS化合物类适合进一步开发用于治疗依赖Shp2疾病的疗法。
