Development of SHP2-selective Phosphatase Inhibitors for Cancer Therapy

Shp 2蛋白酪氨酸磷酸酶（FTP）介导生长因子受体信号传导并调节细胞增殖 对肿瘤生长和转移至关重要的活性。Shp 2被致癌的幽门螺杆菌所利用 CagA蛋白导致胃癌。Shp 2激活突变与发育相关， 疾病努南综合征，并与白血病和实体瘤有关。然而，详细 Shp 2介导细胞信号传导、致癌和转移的机制仍不完全 明白目前没有小分子Shp 2抑制剂可用于靶向治疗和化学治疗。 基因研究。基于分子生物学证据，我们假设Shp 2是一种重要的酶， 癌症靶向治疗的发展。该项目的总体目标是确定小的有机 作为分子靶向癌症治疗的潜在药物的Shp 2-选择性FTP抑制剂分子， 作为Shp 2信号传导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。我们已经确定了Shp 2抑制剂的两个先导化合物。在Aim I中，我们将 基于这些先导化合物合成集中的化学文库，筛选更大的多样性化学物质， 文库，并在体外表征Shp 2抑制剂，以获得具有更好效力、选择性和 药物性质。在目标II中，我们将评估Shp 2抑制剂抑制表皮生长的能力 EGF刺激的Shp 2激活和激活的Shp 2突变体在细胞培养物中的活性， 它们具有脱靶效应和它们在细胞培养物中的稳定性。有前途的Shp 2抑制剂将进一步 在目的III中评价了它们在细胞培养物和肿瘤中抑制转化表型的活性 异种移植这项跨学科的研究将确定有前途的Shp 2选择性抑制剂，并提供 验证Shp 2 FTP作为Shp 2临床开发药物靶点的药理学证据- 靶向癌症治疗。 Lay声明：Shp 2是一种蛋白质，在各种形式的人类发育中起着关键作用。 癌症和其他疾病。我们将发现和表征Shp 2抑制剂。这将奠定基础 为进一步临床开发靶向Shp 2的癌症干预新药提供了许多- 需要化学探针来了解Shp 2在人类疾病中的功能。

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.