A-366

A-366 A chemical Probe for G9a/GLP

This compound is available from SigmaTocris and Cayman Chemical

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 (2nd Tudor domain) with IC50 = 182.6 ± 9.1 nM. 

properties

5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-indol]-2'-amine

Physical and chemical properties for A-366
Molecular weight329.2
Molecular formulaC19H27N3O2
IUPAC name5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-indol]-2'-amine
MollogP3.924
PSA49.37
No. of chiral centres0
No. of rotatable bonds6
No. of hydrogen bond acceptors4
No. of hydrogen bond donors2
  • SMILES:
  • COc1cc2c(cc1OCCCN1CCCC1)N=C(C21CCC1)N
  • InChI:
  • InChI=1S/C19H27N3O2/c1-23-16-12-14-15(21-18(20)19(14)6-4-7-19)13-17(16)24-11-5-10-22-8-2-3-9-22/h12-13H,2-11H2,1H3,(H2,20,21)
  • InChIKey:
  • BKCDJTRMYWSXMC-UHFFFAOYSA-N
selectivity profile

in vitro potency
cell based assay data
references

Discovery and development of potent and selective inhibitors of histone methyltransferase g9aACS 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.

pk properties
co-crystal structures

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Main features

synthetic schemes
materials and methods