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

Sharad K. Verma(GlaxoSmithKline (United States)), Xinrong Tian(GlaxoSmithKline (United States)), Louis V. LaFrance(GlaxoSmithKline (United States)), Céline Duquenne(GlaxoSmithKline (United States)), Dominic Suarez(GlaxoSmithKline (United States)), Kenneth A. Newlander(GlaxoSmithKline (United States)), Stuart P. Romeril(GlaxoSmithKline (United States)), Joelle L. Burgess(GlaxoSmithKline (United States)), Seth W. Grant(GlaxoSmithKline (United States)), James Brackley(GlaxoSmithKline (United States)), Alan P. Graves(GlaxoSmithKline (United States)), D. Scherzer(GlaxoSmithKline (United States)), Art Shu(GlaxoSmithKline (United States)), Christine Thompson(GlaxoSmithKline (United States)), Heidi M. Ott(GlaxoSmithKline (United States)), Glenn S. Van Aller(GlaxoSmithKline (United States)), Carl A. Machutta(GlaxoSmithKline (United States)), Elsie Diaz(GlaxoSmithKline (United States)), Yong Jiang(GlaxoSmithKline (United States)), Neil W. Johnson(GlaxoSmithKline (United States)), Steven D. Knight(GlaxoSmithKline (United States)), Ryan G. Kruger(GlaxoSmithKline (United States)), Michael T. McCabe(GlaxoSmithKline (United States)), Dashyant Dhanak(GlaxoSmithKline (United States)), Peter J. Tummino(GlaxoSmithKline (United States)), Caretha L. Creasy(GlaxoSmithKline (United States)), William H. Miller(GlaxoSmithKline (United States))
ACS Medicinal Chemistry Letters
October 19, 2012
Cited by 376Open Access
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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.


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