Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

中文翻译：

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在癌症模型中具有抗增殖作用的KDM4抑制剂的设计

组蛋白赖氨酸脱甲基酶（KDM）在染色质相关过程的调节中起着至关重要的作用。在这里，我们描述了我们发现的一系列有效的KDM4抑制剂，这些抑制剂在癌症模型中既具有细胞渗透性又具有抗增殖性。通过均相时间分辨荧光测定和质谱检测，验证了化合物处理后组蛋白H3K9me3和H3K36me3的调节。使用基于结构的药物设计对该系列进行优化后，产生了化合物6（QC6352），这是一种有效的KDM4家族抑制剂，在乳腺癌和结肠癌PDX模型中有效。