GSK343 A potent, selective inhibitor of EZH2 with cellular activity

This probe is available from Sigma, Cayman Chemical and Tocris.

For any inquiries please contact proberequests@thesgc.org.

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Overview

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. GlaxoSmithKline has developed a potent, selective, cell-active EZH2 inhibitor, GSK343, and has made this available as a chemical probe as part of the SGC epigenetics initiative. GSK343 inhibits EZH2 with an IC50 of 4nM and is over 1000-fold selective for other HMTs except EZH1 (60-fold selectivity). GSK343 inhibits H3K27 methylation in HCC1806 cells with an IC₅₀ of <200nM as measured by immunofluorescence.

Properties

Structure of N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1-(propan-2-yl)-1H-indazole-4-carboxamide

N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]
-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]
-1-(propan-2-yl)-1H-indazole-4-carboxamide
Click here to download SDF file

Physical and chemical properties
Molecular weight	541.3
Molecular formula	C31H39N7O2
IUPAC name	N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl] -6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl] -1-(propan-2-yl)-1H-indazole-4-carboxamide
logP	3.23
PSA	95.39

SMILES:

CCCC1=C(CNC(=O)C2=C3C=NN(C(C)C)C3=CC(=C2)C2=CC=NC(=C2)N2CCN(C)CC2)C(=O)NC(C)=C1

InChI:

InChI=1S/C31H39N7O2/c1-6-7-23-14-21(4)35-31(40)26(23)18-33-30(39)25-15-24(16-28-27(25)19-34-38(28)20(2)3)22-8-9-32-29(17-22)37-12-10-36(5)11-13-37/h8-9,14-17,19-20H,6-7,10-13,18H2,1-5H3,(H,33,39)(H,35,40)

InChIKey:

ULNXAWLQFZMIHX-UHFFFAOYSA-N

Selectivity Profile

Cell-based Assay Data

GSK343 inhibits H3K27 methylation in HCC1806 cells with an IC50 of <200nM as measured by immunofluorescence.

Biological characterization of GSK343. (a) H3K27me3 imaging in HCC1806 cells treated with DMSO or GSK343 for 72 hours; (b) Dose-response of GSK343-treated HCC 1806 cells.

References

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 Graves, Daryl A. Scherzer, Art Shu, Christine S. Thompson, Heidi Morgan-Ott, Glenn S. Van Aller, Carl A. Machutta, Elsie Diaz, Yong Jiang, Neil W. Johnson, Steven Knight, Ryan G. Kruger, Michael T. McCabe, Dashyant Dhanak, Peter J. Tummino, Caretha L. Creasy and William H. Miller. ACS Med. Chem. Lett., 2012, 3 (12), pp 1091–1096 DOI: 10.1021/ml3003346.