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• W2091646369 abstract "The Shp2 protein tyrosine phosphatase (PTP) mediates signal transduction of growth factor receptors and regulates cellular activities critical to tumor growth and metastasis. In the basal state, the interactions between the N-SH2 and PTP domains keep the phosphatase in an auto inhibited 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. Shp2 is therefore believed to be an important enzyme for targeted cancer therapy. Since no potent and selective Shp2 PTP inhibitor is currently available for chemical biology studies and experimental therapy, we and others have been actively engaged in the search for such agents. In our continuing efforts to develop potent and selective Shp2 inhibitors to serve as both chemical probes to further our understanding of the role and signaling mechanisms of Shp2 in human diseases and as potential drugs for cancer therapy. We will report the screening of a focused library of a set of commercially available salicylic acid derivatives using the in vitro DIFMUP phosphatase assay for their ability to inhibit the Shp2 phosphatase domain. Activity of hits was confirmed using the Biomol Green assay to determine inhibition of dephosphorylation of a Shp2 peptide substrate derived from EphR. One such hit was a thiazole containing salicylic acid that inhibits Shp2 with an IC50 (DIFMUP) of 100 µM. We will report the design and synthesis of salicylic acid libraries along with their benzoic acid counterparts. The most potent compound to date is HM2-08-4 which has an IC50 (DIFMUP) 1.1 µM. Emerging structure-activity relationships as well as modeling and X-ray studies will be discussed. The preliminary use of selected compounds as tools to probe the pharmacological inhibition of Shp2 and elucidate its role in cancer will be described. 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 3248. doi:10.1158/1538-7445.AM2011-3248" @default.
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• W2091646369 date "2011-04-15" @default.
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• W2091646369 title "Abstract 3248: New inhibitors of the Shp2 phosphatase" @default.
• W2091646369 doi "https://doi.org/10.1158/1538-7445.am2011-3248" @default.
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