Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2

  • ACS Med Chem Lett. 2012 Oct 19;3(12):1091-6. doi: 10.1021/ml3003346.
Sharad K Verma  1 ,  Xinrong Tian  1 ,  Louis V LaFrance  1 ,  Céline Duquenne  1 ,  Dominic P Suarez  1 ,  Kenneth A Newlander  1 ,  Stuart P Romeril  1 ,  Joelle L Burgess  1 ,  Seth W Grant  1 ,  James A Brackley  1 ,  Alan P Graves  1 ,  Daryl A Scherzer  1 ,  Art Shu  1 ,  Christine Thompson  1 ,  Heidi M Ott  1 ,  Glenn S Van Aller  1 ,  Carl A Machutta  1 ,  Elsie Diaz  1 ,  Yong Jiang  1 ,  Neil W Johnson  1 ,  Steven D Knight  1 ,  Ryan G Kruger  1 ,  Michael T McCabe  1 ,  Dashyant Dhanak  1 ,  Peter J Tummino  1 ,  Caretha L Creasy  1 ,  William H Miller  1
Affiliations
  • 1. Cancer Epigenetics Discovery Performance Unit, Oncology Research & Development, Protein Dynamics Discovery Performance Unit, Oncology Research & Development, and Platform Technology and Sciences, GlaxoSmithKline Pharmaceuticals , Collegeville, Pennsylvania 19426, United States.
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.

Keywords
EZH2; Epigenetics; H3K27me3; PRC2; SAM-competitive inhibitor; methyltransferase.
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