Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
J Med Chem. 2022 Sep 22;65(18):12200-12218. doi: 10.1021/acs.jmedchem.2c00866. Epub 2022 Sep 12.
Both Src homology-2 domain-containing phosphatase 2 (SHP2) and histone deacetylase (HDAC) are important oncoproteins and potential immunomodulators. In this study, we first observed a synergistic antiproliferation effect of an allosteric SHP2 inhibitor (SHP099) and HDAC inhibitor (SAHA) in MV4-11 cells. Inspired by this result, a series of SHP2/HDAC dual inhibitors were designed based on the pharmacophore fusion strategy. Among these inhibitors, the most potent compound showed excellent inhibitory activities against SHP2 (IC = 20.4 nM) and HDAC1 (IC = 25.3 nM). In particular, compound exhibited improved antitumor activities compared with those of SHP099 and SAHA in vitro and in vivo. Our study also indicated that treatment with could trigger efficient antitumor immunity by activating T cells, enhancing the antigen presentation function and promoting cytokine secretion. To our knowledge, we report the first small molecular SHP2/HDAC dual inhibitor and demonstrate a new strategy for cancer immunotherapy.
Src 同源物-2 结构域包含的磷酸酶 2（SHP2）和组蛋白去乙酰化酶（HDAC）都是重要的癌蛋白和潜在的免疫调节剂。在这项研究中，我们首先观察到别构 SHP2 抑制剂（SHP099）和 HDAC 抑制剂（SAHA）在 MV4-11 细胞中具有协同的抗增殖作用。受此结果启发，我们基于药效团融合策略设计了一系列 SHP2/HDAC 双重抑制剂。在这些抑制剂中，最有效的化合物 对 SHP2（IC = 20.4 nM）和 HDAC1（IC = 25.3 nM）表现出优异的抑制活性。特别是，化合物 在体外和体内均表现出比 SHP099 和 SAHA 更好的抗肿瘤活性。我们的研究还表明，用 治疗可以通过激活 T 细胞、增强抗原呈递功能和促进细胞因子分泌来触发有效的抗肿瘤免疫。据我们所知，我们报告了第一个小分子 SHP2/HDAC 双重抑制剂，并展示了一种癌症免疫治疗的新策略。
