Development of SHP2-selective Phosphatase Inhibitors for Cancer Therapy

Shp2蛋白酪氨酸磷酸酶介导生长因子受体信号转导调节细胞 对肿瘤生长和转移至关重要的活动。致癌幽门螺杆菌利用Shp2 CagA蛋白可导致胃癌。Shp2激活突变与发育相关 Noonan综合征，并与白血病和实体瘤有关。然而，详细的 Shp2介导细胞信号转导、肿瘤发生和转移的机制尚不完全 明白了。目前还没有小分子Shp2抑制剂可用于靶向治疗和化学治疗 基因研究。根据分子生物学证据，我们推测Shp2是一种重要的 发展有针对性的癌症治疗。这个项目的总体目标是识别小型有机 Shp2-选择性ftp抑制剂分子作为分子靶向癌症治疗和治疗的潜在药物 作为Shp2信号机制的化学遗传询问的工具。三个具体目标将是 在目前的研究中所追求的。我们已经确定了两种Shp2抑制剂的先导化合物。在Aim I中，我们将 根据这些先导化合物合成有针对性的化学库，筛选更大的不同化学物质 文库，并在体外鉴定Shp2抑制剂，以获得更好的效力、选择性和 类似毒品的特性。在AIM II中，我们将评估Shp2抑制剂抑制表皮生长的能力。 表皮生长因子(EGF)刺激Shp2激活和激活的Shp2突变体在细胞培养中的活性 它们具有非靶标效应，并且在细胞培养中具有稳定性。有希望的Shp2抑制剂将进一步 在AIM III中评价它们在抑制细胞培养和肿瘤转化表型方面的活性 异种移植物。这项跨学科研究将确定有前景的Shp2选择性抑制剂并提供 Shp2-ftp作为Shp2-2临床开发药物靶点的药理学证据 有针对性的癌症治疗。 Lay声明：Shp2是一种蛋白质，在各种形式的人类发育过程中发挥着关键作用 癌症和其他疾病。我们将发现并鉴定Shp2抑制剂。这将奠定基础 为进一步开发针对Shp2的癌症干预新药并提供更多的 了解Shp2在人类疾病中的功能所需的化学探针。

Shp2 protein tyrosine phosphatase (FTP) mediates growth factor receptor signaling and regulates cellular activities critical to tumor growth and metastasis. Shp2 is employed by the carcinogenic Helicobactor pylori CagA protein to cause gastric cancer. Shp2 activating mutations have been linked to the developmental disorder Noonan syndrome and are associated with leukemias and solid tumors. However, the detailed mechanisms by which Shp2 mediates cell signaling, carcinogenesis and metastasis remain incompletely understood. No small molecule Shp2 inhibitor is currently available for targeted therapy and chemical genetic studies. Based on molecular biology evidence, we postulate that Shp2 is an important enzyme for development of targeted cancer therapy. The overall goal of this project is to identify small organic molecules of Shp2-selective FTP inhibitors as potential agents for molecularly.targeted cancer therapy and as tools for chemical genetic interrogation of Shp2 signaling mechanisms. Three specific aims will be pursued in the current study. We have identified two lead compounds of Shp2 inhibitors. In Aim I, we will synthesize focused chemical libraries based on these lead compounds, screen a larger diverse chemical library, and characterize Shp2 inhibitors in vitro to obtain Shp2 inhibitors with better potency, selectivity, and drug-like properties. In Aim II, we will evaluate Shp2 inhibitors for their ability to inhibit epidermal growth factor (EGF)-stimulated Shp2 activation and activity of an activated Shp2 mutant in cell cultures, whether they have off-target effects, and their stability in cell cultures. Promising Shp2 inhibitors will be further evaluated in Aim III for their activities in inhibition of transformed phenotypes in cell cultures and in tumor xenografts. This interdisciplinary study will identify promising Shp2-selective inhibitors and provide pharmacological evidence for validation of Shp2 FTP as a drug target for clinical development of Shp2- targeted cancer therapy. Lay statement: Shp2 is a protein that plays a critical role in the development of various forms of human cancer and other diseases. We will discover and characterize Shp2 inhibitors. This will lay the foundation for further clinical development of new drugs targeting Shp2 for cancer intervention and provide much- needed chemical probes for understanding the functionality of Shp2 in human diseases.