Center for Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
Eur J Med Chem. 2024 Dec 5;279:116830. doi: 10.1016/j.ejmech.2024.116830. Epub 2024 Sep 5.
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2), a critical regulator of proliferation pathways and immune checkpoint signaling in various cancers, is an attractive target for cancer therapy. Here, we report the discovery of a novel series of substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors. Among them, compound C6 showed excellent inhibitory activity against SHP2 and antiproliferative effect on MV-4-11 cell line with IC values of 0.13 and 3.5 nM, respectively. Importantly, orally administered C6 displayed robust in vivo antitumor efficacy in the MV-4-11 xenograft mouse model (TGI = 69.5 %, 30 mg/kg). Subsequent H&E and Ki67 staining showed that C6 significantly suppressed the proliferation of tumor cells. Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206/Ly6C M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80/CD206 M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 inhibitor worthy of further development.
Src 同源物-2 含有蛋白酪氨酸磷酸酶 2（SHP2）是各种癌症中增殖途径和免疫检查点信号的关键调节剂，是癌症治疗的一个有吸引力的靶点。在这里，我们报告了一系列新型取代吡啶甲酰胺衍生物作为有效的变构 SHP2 抑制剂的发现。其中，化合物 C6 对 SHP2 表现出优异的抑制活性，并对 MV-4-11 细胞系表现出抗增殖作用，IC 值分别为 0.13 和 3.5 nM。重要的是，口服给予 C6 在 MV-4-11 异种移植小鼠模型中显示出强大的体内抗肿瘤疗效（TGI = 69.5%，30 mg/kg）。随后的 H&E 和 Ki67 染色表明 C6 显著抑制了肿瘤细胞的增殖。值得注意的是，流式细胞术、ELISA 和免疫荧光实验表明，C6 可显著降低 CD206/Ly6C M2 样肿瘤相关巨噬细胞（TAMs）的群体、白细胞介素 10（IL-10）的表达水平和 F4/80/CD206 M2 样 TAMs 的数量，表明 C6 可有效缓解 M2 样 TAMs 的激活和浸润。总之，这些结果表明 C6 是一种有前途的 SHP2 抑制剂，值得进一步开发。
