UNC 0646

IC50: 6 nm (G9a IC50); 26 nm (Cellular IC50); 3.3 μM (Cell toxicity EC50)

Histone-lysine N-methyltransferase, H3 lysine-9 specific 3, also known as euchromatic histone-lysine N-methyltransferase 2 (EHMT2) and G9a, is a histone methyltransferase that in humans is encoded by the EHMT2 gene. Protein lysinemethyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histoneH3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53.

In vitro: UNC0646 is reported to be a potent and selective inhibitor of the homologous protein lysine methyltransferases, G9a and GLP (IC50 values are 6 nM and 15 nM for G9a and GLP, respectively). UNC0646 also potently blocks G9a/GLP methyltransferase activity in cells (IC50 = 10 nM in MCF7 cells) and exhibits low cellular toxicity (EC50 = 4.7 μM in MCF7 cells). UNC0646 is selective for G9a/GLP over a range of other protein lysine methyltransferases and protein arginine methyltransferases [1].

In vivo: The authors previously discovered potent and selective G9a/GLP inhibitors including the cellular chemical probe UNC0638, which displays an excellent separation of functional potency and cell toxicity. However, this inhibitor is not suitable for animal studies due to its poor pharmacokinetic (PK) properties. In this study, the authors report the discovery of the first G9a and GLP in vivo chemical probe UNC0642, which not only maintains high in vitro and cellular potency, low cell toxicity, and excellent selectivity, but also displays improved in vivo PK properties, making it suitable for animal studies [2].

References:
[1] Liu F, Barsyte-Lovejoy D, Allali-Hassani A, He Y, Herold JM, Chen X, Yates CM, Frye SV, Brown PJ, Huang J, Vedadi M, Arrowsmith CH, Jin J.  Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. J Med Chem. 2011;54(17):6139-50.
[2] Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, Arrowsmith CH, Brown PJ, Vedadi M, Jin J.  Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem. 2013;56(21):8931-42.


Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines.[Pubmed:21780790]

J Med Chem. 2011 Sep 8;54(17):6139-50.

Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.

UNC0646 is a potent and selective histone methyltransferase G9a inhibitor with an IC50 of 6 nM. UNC0646 is also a potent GLP inhibitor (IC50 <15 nM) and highly selective for G9a/GLP over SETD7, SUV39H2, SETD8 and PRMT3. UNC0646 reduces H3K9me2 levels in MDA-MB-231 cells with an IC50 of 26 nM.

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