Src homology 2 domain-containing phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine phosphatase (PTP) that regulates signal transduction of receptor tyrosine kinases (RTKs). Abnormal SHP2 activity is associated with tumorigenesis and metastasis. Because SHP2 contains multiple allosteric sites, identifying inhibitors at specific allosteric binding sites remains challenging. Here, we used structure-based virtual screening to directly search for the SHP2 “tunnel site” allosteric inhibitor. A novel hit (70) was identified as the SHP2 allosteric inhibitor with an IC₅₀ of 10.2 μM against full-length SHP2. Derivatization of hit compound 70 using molecular modeling-guided structure-based modification allowed the discovery of an effective and selective SHP2 inhibitor, compound 129, with 122-fold improved potency compared to the hit. Further studies revealed that 129 effectively inhibited signaling in multiple RTK-driven cancers and RTK inhibitor-resistant cancer cells. Remarkably, 129 was orally bioavailable (F = 55%) and significantly inhibited tumor growth in haematological malignancy. Taken together, compound 129 developed in this study may serve as a promising lead or candidate for cancers bearing RTK oncogenic drivers and SHP2-related diseases.

Src 同源性 2 结构域磷酸酶 2 (SHP2) 是一种细胞质蛋白酪氨酸磷酸酶 (PTP)，可调节受体酪氨酸激酶 (RTK) 的信号转导。异常的 SHP2 活性与肿瘤发生和转移有关。由于 SHP2 包含多个变构位点，因此在特定变构结合位点识别抑制剂仍然具有挑战性。在这里，我们使用基于结构的虚拟筛选来直接搜索 SHP2“隧道站点”变构抑制剂。一种新的命中 (70) 被确定为具有 IC _{50的 SHP2 变构抑制剂}10.2 μM 对全长 SHP2。使用分子建模指导的基于结构的修饰对命中化合物 70 进行衍生化，从而发现了一种有效且具有选择性的 SHP2 抑制剂化合物 129，与命中化合物相比，其效力提高了 122 倍。进一步的研究表明，129 有效地抑制了多种 RTK 驱动的癌症和 RTK 抑制剂耐药癌细胞的信号传导。值得注意的是，129 具有口服生物利用度 ( F  = 55%)，并显着抑制血液恶性肿瘤的肿瘤生长。综上所述，本研究开发的化合物 129 可作为具有 RTK 致癌驱动因素的癌症和 SHP2 相关疾病的有前途的先导化合物或候选化合物。