青少年粒单细胞白血病（JMML）和急性髓系白血病(AML)等髓系白血病临床无有效治疗手段。E76K突变型SHP2对JMML和AML发生和发展有重要的促进作用，是潜在的个性化治疗靶点。包括SHP2在内的PTP抑制剂由于选择性和生物利用度差等问题无法成药。变构抑制剂为解决SHP2抑制剂选择性和生物利用度差等问题提供新方向。针对JMML和AML的临床需求，前期通过E76K突变和野生型的SHP2组合高通量筛选，发现两类高选择性E76K突变型SHP2抑制剂，与催化活性域以外区域结合的，为发现变构抑制剂提供物质基础。本项目拟运用基于结构和基于片段的药物设计技术、常规合成技术、微反应技术、酶和细胞活性评价技术，开展E76K突变型SHP2变构抑制剂构效关系研究；采用质谱分析技术研究抑制剂的结合模式；在细胞和动物水平评价高活性、高选择性SHP2抑制剂的抗髓系白血病效果；为抗白血病药物研究提供物质和理论支持。

Myelomonocytic leukemia, including juvenile myelomonocytic leukemia (JMML) and actue myelomonocytic leukemia (AML), lack effective therapeutic interventions. Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) E76K mutant is associated with 35% of patients with JMML and 6.6% of patients with AML and can be a potential personal therapeutic target against myelomonocytic leukemia. The challenges of developing protein tyrosine phosphatase (PTP) inhibitors as drugs include selectivity and bioavailability. Allosteric inhibitors may offer opportunities to avoid the drug discovery challenges related to the polarity and homology of the orthosteric binding pocket of SHP2, thereby advancing the drug discovery process for SHP2 inhibitors. With a long-term focus on developing clinical candidates targeting JMML and AML, we propose to identify two allosteric inhibitors of the SHP2 E76K mutant with novel scaffolds from high-throughput screening against both mutant and wild type enzymes. We will use structure-based drug design and fragment-based drug design in conjunction with flow chemistry and batch chemistry to synthesize a focused yet chemically diverse library, then study the structure–activity relationships of potentially specific inhibitors of the SHP2 E76K mutant. We will then identify the binding mechanisms of the selected allosteric inhibitors using mass spectrometry and evaluate their antileukemic activities using cell and animal assays. We believe that this project constitutes a new strategy for antileukemic drug discovery.