Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, School of Chemical Science and Technology, School of Pharmacy, School of Life Sciences, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China.
Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China.
Bioorg Med Chem. 2024 Nov 15;114:117945. doi: 10.1016/j.bmc.2024.117945. Epub 2024 Oct 16.
Histone lysine demethylase 4D (KDM4D) is a critical player in the regulation of tumorigenesis, emerging as a potential target for developing anti-tumor agents. In this study, a series of KDM4D inhibitors containing the 4,6-diarylquinoxaline scaffold were prepared based on the previously discovered hit compound QD-1. Among these inhibitors, 33a was the most potent compound, with an IC value of 0.62 μM. In an in vitro assay, 33a showed a superior ability to inhibit the viability of liver cancer Huh-7 cells with IC = 5.23 μM. 33a exhibits significant effects in inhibiting cell cycle progression and proliferation of liver cancer cells, as well as suppressing cell migration. This work provided a promising scaffold for developing KDM4D inhibitors, as well as a lead compound for the development of anti-tumor drugs targeting KDM4D.
组蛋白赖氨酸去甲基化酶 4D（KDM4D）是肿瘤发生调控中的关键因子，有望成为开发抗肿瘤药物的潜在靶点。本研究基于先前发现的先导化合物 QD-1，设计并合成了一系列含有 4,6-二芳基喹喔啉骨架的 KDM4D 抑制剂。在所合成的抑制剂中，化合物 33a 对 KDM4D 的抑制活性最强，IC 值为 0.62 μM。在体外实验中，化合物 33a 对肝癌 Huh-7 细胞的半数抑制浓度（IC）值为 5.23 μM，表现出较强的抑制细胞活力的能力。33a 能显著抑制肝癌细胞的细胞周期进程和增殖，并能抑制细胞迁移。本研究为开发 KDM4D 抑制剂提供了有前景的骨架，也为开发针对 KDM4D 的抗肿瘤药物提供了先导化合物。
