SHP2 是由PTPN11基因编码的蛋白酪氨酸磷酸酶，在细胞生长、增殖、分化中具有重要作用。PTPN11基因突变会导致多种疾病的发生。其突变体已成为潜在的靶标。35%的JMML患者与PTPN11基因突变相关且是预后的不良因素。目前还无药可治且死亡率高。本项目选择与JMML密切相关的SHP2激活突变体D61G、E76K为研究受体，基于受体的结构，设计、合成选择性抑制剂并进行活性验证。该抑制剂的研究能为靶向治疗JMML及相关疾病提供先导物，为疾病的分类诊断提供特异性底物。申请人前期研究，已经获得E76K抑制剂D3（IC50为2.5uM），建立了相应的酶及细胞筛选模型。本项目将在已有工作的基础上，以提高选择性及活性为重点，通过高通量虚拟筛选及对活性化合物D3结构优化，设计、合成目标化合物并在酶、细胞及动物水平进行活性验证；最终筛出高活性及选择性的抑制剂。为JMML及相关疾病的精准治疗提供先导物。

The PTPN11 gene encodes Src homology 2 domain-containing phosphatase 2 (SHP2), which plays an important role in mediating multiple downstream biological responses, such as proliferation and/or survival, adhesion, and migration. The mutations in SHP-2 are associated with a variety of diseases and therefore have becoming new drug targets. Germline gain-of-function SHP2 mutations cause 35% of juvenile myelomonocytic leukemia (JMML) and were the prognosis of adverse factors. There is no drug available for JMML, which lead to high death rate. This study is focused on the SHP2 mutants D61G and E76K, which are closely related to JMML. Based on the structure of SHP2 mutants D61G and E76K, selective inhibitors were designed, synthesized, and the bioactivities of these compounds were tested. Studies on selective SHP2 mutants inhibitors may generate leading compounds for targeted therapy JMML and provide specific substrates for studies on the classification of related disease diagnosis. Our team has found a novel molecule named D3 targeting E76K in early work as the lead compound with IC50 2.5uM and built enzyme and cellular models. The key point of this study is to improve the potential and selectivity of the hit compound. The target compounds would be obtained by virtual screening the inhibitor library and modification the lead compound D3; The biological activities and the selectivity were verified on the enzyme, cellular and animal level; Finally, the highly potent and specific inhibitors of the SHP2 mutants were gained. The study here may pave the way for discovering the lead compounds for the targeted therapy and diagnosis of JMML.