具有癌症模型抗增殖作用的KDM4抑制剂的设计
Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.
作者信息
Chen Young K, Bonaldi Tiziana, Cuomo Alessandro, Del Rosario Joselyn R, Hosfield David J, Kanouni Toufike, Kao Shih-Chu, Lai Chon, Lobo Neethan A, Matuszkiewicz Jennifer, McGeehan Andrew, O'Connell Shawn M, Shi Lihong, Stafford Jeffrey A, Stansfield Ryan K, Veal James M, Weiss Michael S, Yuen Natalie Y, Wallace Michael B
机构信息
Celgene Quanticel Research, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
出版信息
ACS Med Chem Lett. 2017 Jul 27;8(8):869-874. doi: 10.1021/acsmedchemlett.7b00220. eCollection 2017 Aug 10.
Abstract
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 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.
摘要
组蛋白赖氨酸去甲基化酶（KDMs）在染色质相关过程的调控中起着至关重要的作用。在此，我们描述了我们发现的一系列强效KDM4抑制剂，它们在癌症模型中具有细胞渗透性且具有抗增殖作用。通过均相时间分辨荧光测定法和质谱检测验证了化合物处理后组蛋白H3K9me3和H3K36me3的调节情况。使用基于结构的药物设计对该系列进行优化，得到了化合物（QC6352），这是一种强效的KDM4家族抑制剂，在乳腺癌和结肠癌PDX模型中有效。
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