Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, China.
Department of Cell Biology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China.
Bioorg Chem. 2020 Jul;100:103875. doi: 10.1016/j.bioorg.2020.103875. Epub 2020 Apr 25.
SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers. Therefore, the development of SHP2 inhibitors has attracted extensive attention. In this study, based on the known inhibitor 1 (SHP099), novel SHP2 inhibitors were designed by means of scaffold hopping, and 35 pyridine derivatives as SHP2 inhibitors were found. The in vitro enzyme activity assay was performed on these compounds, and multiple selective SHP2 inhibitors with activity potency similar to that of SHP099 were obtained. Among them, compound (2-(4-(aminomethyl)piperidin-1-yl)-5-(2,3-dichlorophenyl)pyridin-3-yl)methanol (11a) was the most potent and highly selective SHP2 inhibitor with an in vitro enzyme activity IC value of 1.36 μM. Fluorescence titration assay verified that 11a bound directly to SHP2 protein. Subsequently, cell assay of representative compounds showed that these compounds could effectively inhibit the proliferation of Ba/F cells. In addition, the pharmacokinetic characteristics of the designed compounds were analyzed by the in silico ADMET prediction. Molecular docking study provided more detailed information on the binding mode of compounds and SHP2 protein. In brief, this study reported for the first time that pyridine derivatives as novel SHP2 inhibitors had good inhibitory activity and selectivity, providing new clues for the development of small molecule SHP2 inhibitors.
SHP2 是一种非受体蛋白酪氨酸磷酸酶，由 PTPN11 基因编码，它影响包括 RAS-ERK、PI3K-AKT 和 JAK-STAT 在内的多种信号通路的转导。SHP2 在程序性细胞死亡途径（PD-1/PD-L1）中也发挥着重要作用。研究表明，SHP2 与多种癌症有关，包括乳腺癌、肝癌和胃癌。因此，SHP2 抑制剂的开发引起了广泛关注。在本研究中，基于已知抑制剂 1（SHP099），通过骨架跃迁的方法设计了新型 SHP2 抑制剂，并发现了 35 种吡啶衍生物作为 SHP2 抑制剂。对这些化合物进行了体外酶活性测定，得到了多种与 SHP099 活性相当的选择性 SHP2 抑制剂。其中，化合物（2-(4-(氨甲基)哌啶-1-基)-5-(2,3-二氯苯基)吡啶-3-基)甲醇（11a）是最有效的和高度选择性的 SHP2 抑制剂，其体外酶活性 IC 值为 1.36 μM。荧光滴定实验验证了 11a 直接与 SHP2 蛋白结合。随后，代表性化合物的细胞实验表明，这些化合物能够有效抑制 Ba/F 细胞的增殖。此外，通过计算机 ADMET 预测分析了设计化合物的药代动力学特征。分子对接研究为化合物与 SHP2 蛋白的结合模式提供了更详细的信息。总之，本研究首次报道了吡啶衍生物作为新型 SHP2 抑制剂具有良好的抑制活性和选择性，为小分子 SHP2 抑制剂的开发提供了新的线索。
