title: Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2.
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.
authors.affiliation: 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.
authors.forename: Sharad K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: 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.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Louis V
authors.initials: LV
authors.lastname: LaFrance
authors.affiliation: 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.
authors.forename: Céline
authors.initials: C
authors.lastname: Duquenne
authors.affiliation: 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.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Suarez
authors.affiliation: 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.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Newlander
authors.affiliation: 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.
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Romeril
authors.affiliation: 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.
authors.forename: Joelle L
authors.initials: JL
authors.lastname: Burgess
authors.affiliation: 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.
authors.forename: Seth W
authors.initials: SW
authors.lastname: Grant
authors.affiliation: 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.
authors.forename: James A
authors.initials: JA
authors.lastname: Brackley
authors.affiliation: 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.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Graves
authors.affiliation: 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.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scherzer
authors.affiliation: 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.
authors.forename: Art
authors.initials: A
authors.lastname: Shu
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Thompson
authors.affiliation: 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.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Ott
authors.affiliation: 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.
authors.forename: Glenn S Van
authors.initials: GS
authors.lastname: Aller
authors.affiliation: 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.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Machutta
authors.affiliation: 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.
authors.forename: Elsie
authors.initials: E
authors.lastname: Diaz
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Knight
authors.affiliation: 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.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Kruger
authors.affiliation: 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.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCabe
authors.affiliation: 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.
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.affiliation: 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.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.affiliation: 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.
authors.forename: Caretha L
authors.initials: CL
authors.lastname: Creasy
authors.affiliation: 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.
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
keywords: EZH2; Epigenetics; H3K27me3; PRC2; SAM-competitive inhibitor; methyltransferase