Abstract：
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 IC50 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.
摘要：
核受体结合SET结构域（NSD）蛋白是一类组蛋白赖氨酸甲基转移酶，涉及多种癌症类型，异常表达和参与癌症相关信号通路。在这项研究中,通过基于结构的虚拟筛选,针对NSD的SET结构域鉴定了包括化合物2和3的一系列小分子化合物。我们的先导化合物3在体外对NSD2-SET和NSD3-SET表现出有效的抑制活性，IC50为0.81μM和0.84μM，分别,并有效抑制组蛋白H3赖氨酸36二甲基化，并在100nM时降低非小细胞肺癌细胞中NSD靶向基因的表达。化合物3抑制H460和H1299非小细胞肺癌细胞中的细胞增殖并降低克隆性，并诱导s期细胞周期停滞和凋亡。这些数据使我们的化合物成为研究NSD在癌症中的生物学作用的有价值的工具包。
