A-366 - CAS 1527503-11-2
Catalog number: 1527503-11-2
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
A-366 is peptide-competitive inhibitor of the G9a/GLP histone lysine methyltransferase (IC50 = 3.3 nM) and is approximately 1,000-fold selective over other methyltransferases.
Cream solid
5'-methoxy-6'-(3-pyrrolidin-1-ylpropoxy)spiro[cyclobutane-1,3'-indole]-2'-amine A-366 CHEMBL3109630 A 366 GTPL8238 SCHEMBL17106564 BDBM50446376 ZINC95921314 AKOS024458525 CS-4644 HY-12583 B4947 5'-methoxy-6'-[3-(pyrrolidin-1-yl)propoxy]spiro[cyclobutane-1
Soluble to 100 mM in 1eq. HCl and to 100 mM in DMSO
Store in a cool and dry place and at 0 - 4℃ for short term (days to weeks) or -57℃ for long term (months to years).
Shelf Life:
2 years
Boiling Point:
533.6±60.0 °C | Condition: Press: 760 Torr
1.29±0.1 g/cm3
Canonical SMILES:
1.Discovery and development of potent and selective inhibitors of histone methyltransferase g9a.
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 ACS Med Chem Lett. 2014 Jan 2;5(2):205-9. doi: 10.1021/ml400496h. eCollection 2014 Feb 13.
G9a is a histone lysine methyltransferase responsible for the methylation of histone H3 lysine 9. The discovery of A-366 arose from a unique diversity screening hit, which was optimized by incorporation of a propyl-pyrrolidine subunit to occupy the enzyme lysine channel. A-366 is a potent inhibitor of G9a (IC50: 3.3 nM) with greater than 1000-fold selectivity over 21 other methyltransferases.
2.Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice.
Wang DY;Kosowan J;Samsom J;Leung L;Zhang KL;Li YX;Xiong Y;Jin J;Petronis A;Oh G;Wong AHC Acta Pharmacol Sin. 2018 May;39(5):866-874. doi: 10.1038/aps.2017.190. Epub 2018 Feb 8.
Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety-related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.
3.The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia.
Pappano WN;Guo J;He Y;Ferguson D;Jagadeeswaran S;Osterling DJ;Gao W;Spence JK;Pliushchev M;Sweis RF;Buchanan FG;Michaelides MR;Shoemaker AR;Tse C;Chiang GG PLoS One. 2015 Jul 6;10(7):e0131716. doi: 10.1371/journal.pone.0131716. eCollection 2015.
Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia.
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CAS 1527503-11-2 A-366

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