Abstract 734: Development of small molecule inhibitors of the phosphatase Shp2 by fragment screening

Abstract

Abstract Protein tyrosine phosphorylation, which is controlled by tyrosine kinase (PTK) and tyrosine phosphatase (PTP), regulates numerous cellular processes, including proliferation, survival, differentiation, migration and apoptosis. Accumulating evidence has shown that defective function of PTPs leads to aberrant protein phosphorylation, which is associated with many humane diseases, including cancer. Src homology 2 phosphatase-2 (Shp2) is a cytoplasmic, nonreceptor protein tyrosine phophatase. It is the first proto-oncogene identified in the PTP superfamily. The structure of Shp2 consists of two SH2 (N-SH2 and C-SH2) domains, a single PTP region and a C-terminal hydrophilic tail. In the basal state, Shp2 displays a low catalytic activity due to close interactions between the N-SH2 and PTP domains that keep the phosphatase in an autoinhibited closed conformation. Upon growth factor or cytokine stimulation, the SH2 domains of Shp2 binds to tyrosine phosphorylated docking proteins such as Gab1 and Gab2, which activates Src, Ras, and the Erk1/2 (Erk) mitogen-activated protein (MAP) kinase pathway. Shp2 gain-of-function mutations are found in leukemias and solid tumors and are linked to Noonan syndrome. Although Shp2 is involved in pathogenesis of human cancers, it is not clear how Shp2 mediates tumorigenesis. To aid chemical biology studies and ultimately experimental therapy, we have been actively engaged in the search potent and selective Shp2 inhibitors. We will describe the results of a fragment-based screen as a method for identifying Shp2 inhibitors. The fragment libraries were both purchased and constructed in-house with a bias towards compounds that would potentially function as phosphotyrosine mimics. This has revealed compounds with moderate to low activity (IC50 200-500 µM) that have served as the starting pints for fragment-to-lead development. The emerging structure-activity relationships will be discussed as well as synthesis, modeling and X-ray studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 734.