原癌蛋白RAS是驱动肺癌发生发展的关键基因，通过蛋白酪氨酸磷酸酶SHP2调控其信号传导是治疗肺癌的重要途径。对SHP2的磷酸化调控机制了解有限，限制了其对RAS信号通路调控的认识。我们前期首次发现了一个黄烷酮类小分子(S)-10通过靶向SHP2中过去认为无法实现特异性的磷酸酶结构域，实现了特异性抑制其活性及一个我们新发现的丝氨酸位点磷酸化。因此，本课题拟通过构效关系研究，提高(S)-10的活性和特异性；通过测定(S)-10与SHP2复合物晶体结构等方法明确其结合方式，发现新的SHP2变构调控位点；研究SHP2的酪氨酸和丝氨酸磷酸化调控RAS信号通路的作用机制，探讨变构对SHP2的磷酸化及其活性和底物特异性的作用机制；研究SHP2的磷酸化在调控RAS突变肺癌发生和转移中的功能。旨在阐明变构调控SHP2的磷酸化，影响其活性和底物识别的新机制及其在肺癌发生中的功能，提供肺癌诊断和治疗的新策略。

Oncogenic RAS is a key driver gene leading to lung cancer, which is regulated by protein tyrosine phosphatase SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) and inhibition of it is an important strategy to treat RAS mutated cancers including lung cancer. However, the mechanism of SHP2 phosphorylation regulation is still unclear, which limits our understanding of function of SHP2 on RAS signaling. Previously we identified a flavanone (S)-10 as a specific inhibitor of SHP2 by targeting its protein tyrosine phosphatase (PTP) catalytic domain and it inhibited the phosphorylation occurred in a newly identified serine in SHP2. In this study we will use (S)-10 as a probe to study its structure-activity relationship to increase its activity and specificity in targeting SHP2; clarify the binding mode of (S)-10 on SHP2 by X-ray crystallographic analysis of (S)-10-SHP2 complex to find out new allosteric site of SHP2; study the mechanism of SHP2 tyrosine phosphorylation and serine phosphorylation in the modulation of RAS signaling, discover the allosteric regulation in SHP2 phosphorylation and subsequent SHP2 activity and substrate recognition; elucidate the function of SHP2 phosphorylation in the regulation of RAS mutated lung cancer carcinogenesis and metastasis. The purpose of this study is to reveal the new mechanism and function of allosteric modulation in SHP2 phosphorylation and subsequent SHP2 activity and substrate recognition in lung cancer carcinogenesis, and provide new strategies for the diagnosis and treatment of lung cancer.