新型吖啶基 LSD1 抑制剂增强胃癌的免疫应答。
Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer.
机构信息
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan Province, China.
Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, China.
出版信息
Eur J Med Chem. 2023 Nov 5;259:115684. doi: 10.1016/j.ejmech.2023.115684. Epub 2023 Jul 29.
Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.
最近，组蛋白赖氨酸特异性去甲基化酶 1（LSD1）已成为癌症免疫治疗的一个新兴且有前景的靶点。在此，我们基于先前报道的 LSD1 抑制剂 DXJ-1（也称为 6x），通过结构优化，鉴定了一系列新型吖啶基 LSD1 抑制剂。其中，化合物 5ac 对 LSD1 的抑制活性显著增强，IC 值为 13 nM，约比 DXJ-1（IC = 73 nM）强 4.6 倍。分子对接研究表明，化合物 5ac 可以很好地结合到 LSD1 的活性部位。进一步的机制研究表明，化合物 5ac 抑制了胃癌细胞的干性和迁移，并降低了 BGC-823 和 MFC 细胞中 PD-L1 的表达。更重要的是，用化合物 5ac 处理 BGC-823 细胞后，T 细胞的杀伤作用增强。此外，化合物 5ac 在小鼠体内也抑制了肿瘤的生长。综上所述，5ac 可作为增强胃癌免疫反应的一种有前途的候选药物。
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