Shp2 Inhibitor Activity Of Estramustine Phosphate And Its Triterpenoid Analogues

Shp2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. Shp2 mediates proliferative signaling induced by growth factors. Gain-of-function PTPN11 mutations that encode constitutively active Shp2 are leukemic oncogenes. In a continuing effort to identify new Shp2 PTP inhibitors, we screened a small molecule library comprising the National Cancer Institute (NCI) Approved Oncology Drug set and the NIH Clinical Collection. After evaluation of initial hits, estramustine phosphate was verified as a Shp2 PTP inhibitor. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triperpenoids, enoxolone and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors. These findings point to a rich natural source for discovery of lead compounds of novel PTP inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3239. doi:10.1158/1538-7445.AM2011-3239