蛋白酪氨酸磷酸酶SHP2在细胞信号转导过程中起着重要的作用，参与细胞的生长、分化、代谢、运动和凋亡，作为潜在的抗肿瘤治疗靶点备受关注。选择性抑制剂能为研究SHP2在细胞信号通路中的生物功能及作用机制提供工具化合物，为抗肿瘤药物研究提供先导化合物。选择性和透膜性是SHP2抑制剂设计过程中必须考虑的关键问题。我们在前期研究过程中，发现三类具有全新分子骨架的SHP2抑制剂，其中部分抑制剂不含大极性基团，但选择性有待提高。本项目拟开展SHP2抑制剂的优化工作，运用基于结构的药物设计、基于片段的药物设计及组合化学等理念，借鉴原位点击化学技术在其他领域运用的成功经验，利用合成化学、活性筛选等手段，实施化学结构多样性的化合物库的设计、合成以及活性筛选，获得系统的构效关系信息，发现选择性高、活性强、透膜性好的SHP2抑制剂，为设计新型SHP2抑制剂提供新思路。

SHP2 is of importance for the regulation of essential cellular processes that control growth, differentiation, metabolism, motility and apoptosis and has potential as a drug target. The SHP2 specific small molecule agents to modulate cellular processes through direct interactions with SHP2 offer a number of attractive attributes to novel antitumor therapeutics. The two key points are to improve the selectivity and bioavailability of small molecular SHP2 inhibitors. Based on our previous studies, we identified several compounds with SHP2 inhibitory activity and selectivity, and our project will start with three hit compounds with novel scaffolds, use structure-based drug design and fragment-based drug design and in situ click chemistry to synthesize a focused library with chemical diversity, study the structure-activity relationships to obtain potentially specific inhibitors for SHP2, offer a new strategy to design novel inhibitors against SHP2.