Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041, China.
Eur J Med Chem. 2021 Nov 5;223:113662. doi: 10.1016/j.ejmech.2021.113662. Epub 2021 Jun 26.
Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D.
组蛋白赖氨酸去甲基酶 4D（KDM4D）在肿瘤发生、进展和耐药性的调节中起着重要作用，已被认为是癌症治疗的潜在靶点。然而，仍然缺乏有效的、选择性的 KDM4D 抑制剂。在这项研究中，我们报告了一类新的 KDM4D 抑制剂，其含有 2-(芳基（吡咯烷-1-基）甲基）苯酚骨架，通过 AlphaLisa 筛选、结构优化和构效关系分析鉴定。在这些抑制剂中，24s 是最有效的，IC 值为 0.023 ± 0.004 μM。该化合物对 KDM4D 的选择性比对 KDM4A 以及其他 JMJD 亚家族成员高 1500 多倍，表明对 KDM4D 具有良好的选择性。动力学分析表明，24s 不占据 2-氧戊二酸结合口袋。在体外实验中，24s 显著抑制结直肠癌细胞（CRC）的增殖和迁移。总的来说，这项研究鉴定了一种用于探索 KDM4D 生物学功能的良好工具化合物，以及一种用于针对 KDM4D 进行药物发现的良好先导化合物。
