A-366 A chemical Probe for G9a/GLP

This compound is available from Sigma, Tocris and Cayman

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Overview

A collaboration between the SGC and Abbvie has resulted in the discovery of A-366, a chemical Probe for G9a/GLP. A-366 is a potent inhibitor of G9a/GLP with IC50 3 nM and > 100-fold selectivity over other methyltransferases and other non-epigenetic targets. A-366 has been shown to inhibit H3K9 methylation in cells with an IC50 of 100 nM and exhibits minimal cellular toxicity compared with previous quinazoline-based probes.

A recent study by Wagner et al. (PMID: 26893353) showed that A-366 displaces H3K4me3 from Spindlin1 (2^nd Tudor domain) with IC₅₀ = 182.6 ± 9.1 nM.

Selectivity Profile

Cellbased Assay Data

Co-crystal structures

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Main features
1. Overall structure of A-366 and SAM with G9a
2. A-366 occupies the lysine binding site of G9a

References

Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med Chem Lett. 2014 Jan 2;5(2):205-9
Sweis RF, Pliushchev M, Brown PJ, Guo J, Li F, Maag D, Petros AM, Soni NB, Tse C, Vedadi M, Michaelides MR, Chiang GG, Pappano WN.

The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia. PLoS ONE 10(7): e0131716. doi:10.1371/journal. pone.0131716. William N. Pappano, Jun Guo, Yupeng He, Debra Ferguson, Sujatha Jagadeeswaran, Donald J. Osterling, Wenqing Gao, Julie K. Spence, Marina Pliushchev, Ramzi F. Sweis, Fritz G. Buchanan, Michael R. Michaelides, Alexander R. Shoemaker, Chris Tse, Gary G. Chiang.

Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. Nucleic Acids Res. 2016 Feb 17.
Wagner T, Greschik H, Burgahn T, Schmidtkunz K, Schott AK, McMillan J, Baranauskienė L, Xiong Y, Fedorov O, Jin J, Oppermann U, Matulis D,Schüle R, Jung M.