Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

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 comp...

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Veröffentlicht in:	ACS medicinal chemistry letters 2017-08, Vol.8 (8), p.869-874
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	60 APPLIED LIFE SCIENCES cancer epigenetics histone demethylase JMJD2 KDM4 Letter synthesis
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Zusammenfassung:	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.
ISSN:	1948-5875 1948-5875
DOI:	10.1021/acsmedchemlett.7b00220