2. Academic Validation
  3. Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

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

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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