Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2

Sharad K. Verma, Xinrong Tian, Louis V. Lafrance, Céline Duquenne, Dominic P. Suarez, Kenneth A. Newlander, Stuart P. Romeril, Joelle L. Burgess, Seth W. Grant, James A. Brackley, Alan P. Graves, Daryl A. Scherzer, Art Shu, Christine Thompson, Heidi M. Ott, Glenn S. Van Aller, Carl A. MacHutta, Elsie Diaz, Yong Jiang, Neil W. JohnsonSteven D. Knight, Ryan G. Kruger, Michael T. McCabe, Dashyant Dhanak, Peter J. Tummino, Caretha L. Creasy, William H. Miller

Research output: Contribution to journalArticle

Abstract

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-Active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.

Original languageEnglish (US)
Pages (from-to)1091-1096
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume3
Issue number12
DOIs
StatePublished - Dec 13 2012
Externally publishedYes

Keywords

  • EZH2
  • Epigenetics
  • H3K27me3
  • PRC2
  • SAM-competitive inhibitor
  • methyltransferase

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Verma, S. K., Tian, X., Lafrance, L. V., Duquenne, C., Suarez, D. P., Newlander, K. A., Romeril, S. P., Burgess, J. L., Grant, S. W., Brackley, J. A., Graves, A. P., Scherzer, D. A., Shu, A., Thompson, C., Ott, H. M., Van Aller, G. S., MacHutta, C. A., Diaz, E., Jiang, Y., ... Miller, W. H. (2012). Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2. ACS Medicinal Chemistry Letters, 3(12), 1091-1096. https://doi.org/10.1021/ml3003346