Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

  • ACS Med Chem Lett. 2017 Jul 27;8(8):869-874. doi: 10.1021/acsmedchemlett.7b00220.
Young K Chen  1 ,  Tiziana Bonaldi  2 ,  Alessandro Cuomo  2 ,  Joselyn R Del Rosario  1 ,  David J Hosfield  3 ,  Toufike Kanouni  1 ,  Shih-Chu Kao  4 ,  Chon Lai  1 ,  Neethan A Lobo  4 ,  Jennifer Matuszkiewicz  1 ,  Andrew McGeehan  4 ,  Shawn M O'Connell  1 ,  Lihong Shi  1 ,  Jeffrey A Stafford  1 ,  Ryan K Stansfield  1 ,  James M Veal  1 ,  Michael S Weiss  4 ,  Natalie Y Yuen  4 ,  Michael B Wallace  1
Affiliations
  • 1. Celgene Quanticel Research, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
  • 2. Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
  • 3. Ben May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, United States.
  • 4. Celgene Quanticel Research, 1500 Owens Street, Suite 500, San Francisco, California 94158, United States.
PMID: 28835804 DOI: 10.1021/acsmedchemlett.7b00220
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.

Keywords
Epigenetics; JMJD2; KDM4; cancer; histone demethylase; synthesis.
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