Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

Young K. Chen, Tiziana Bonaldi, Alessandro Cuomo, Joselyn R. Del Rosario, David J. Hosfield, Toufike Kanouni, Shih Chu Kao, Chon Lai, Neethan A. Lobo, Jennifer Matuszkiewicz, Andrew McGeehan, Shawn M. O'Connell, Lihong Shi, Jeffrey A. Stafford, Ryan K. Stansfield, James M. Veal, Michael S. Weiss, Natalie Y. Yuen, Michael B. Wallace

Research output: Contribution to journalArticlepeer-review

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 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

Original languageEnglish
Pages (from-to)869-874
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 10 2017

Keywords

  • cancer
  • Epigenetics
  • histone demethylase
  • JMJD2
  • KDM4
  • synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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