Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, 213001, China.
Primary Biotechnology Co., Ltd., Changzhou, 213125, China.
Eur J Med Chem. 2024 Mar 15;268:116264. doi: 10.1016/j.ejmech.2024.116264. Epub 2024 Feb 20.
Nuclear receptor binding SET domain (NSD) proteins are a class of histone lysine methyltransferases and implicated in multiple cancer types with aberrant expression and involvement of cancer related signaling pathways. In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC of 0.81 μM and 0.84 μM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung cancer cells, and induces s-phase cell cycle arrest and apoptosis. These data establish our compounds as a valuable tool-kit for the study of the biological roles of NSDs in cancer.
核受体结合 SET 域（NSD）蛋白是一类组蛋白赖氨酸甲基转移酶，与多种癌症类型的异常表达和涉及癌症相关信号通路有关。在这项研究中，通过基于结构的虚拟筛选，针对 NSDs 的 SET 域鉴定出了一系列小分子化合物，包括化合物 2 和 3。我们的先导化合物 3 对 NSD2-SET 和 NSD3-SET 的体外抑制活性分别为 0.81μM 和 0.84μM，有效抑制非小细胞肺癌细胞中的组蛋白 H3 赖氨酸 36 二甲基化，并在 100nM 时降低 NSDs 靶向基因的表达。化合物 3 抑制细胞增殖并降低 H460 和 H1299 非小细胞肺癌细胞的集落形成能力，诱导 S 期细胞周期停滞和细胞凋亡。这些数据为研究 NSDs 在癌症中的生物学作用提供了有价值的工具包。
