MedKoo product information:

UNC-0638

Description of UNC-0638: UNC0638 is an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation. (source: Nat Chem Biol. ; 7(8): 566–574. doi:10.1038/nchembio.599.).

Current developer: University of North Carolina at Chapel Hill.

UNC0638 was a potent G9a (IC50 < 15 nM (n = 4)) and GLP inhibitor (IC50 = 19 ± 1 nM (n = 2)) in these SAHH-coupled assays (Table 1). An endoproteinase-coupled microfluidic capillary electrophoresis (MCE) assay, which is orthogonal and complementary to the SAHH-coupled assay, was also used to evaluate G9a inhibition by UNC0638, yielding an IC50 < 10 nM (n = 3). In addition, UNC0638 displaced
a fluorescein-labeled 15-mer H3 peptide (residues 1–15) with high efficiency in a G9a fluorescence-polarization assay, suggesting that UNC0638 binds in the substrate peptidebinding site of G9a. UNC0638 also stabilized G9a and GLP in differential scanning fluorimetry (DSF) experiments, with Tm shifts of 4 °C and 8 °C, respectively, consistent with high-affinity binding.

1: Machleidt T, Robers MB, Hermanson SB, Dudek JM, Bi K. TR-FRET cellular assays for interrogating posttranslational modifications of histone H3. J Biomol Screen. 2011 Dec;16(10):1236-46. Epub 2011 Oct 4. PubMed PMID: 21972037.

2: Hauser AT, Jung M. Chemical probes: sharpen your epigenetic tools. Nat Chem Biol. 2011 Jul 18;7(8):499-500. doi: 10.1038/nchembio.615. PubMed PMID: 21769094.

3: Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011 Jul 10;7(8):566-74. doi: 10.1038/nchembio.599. Erratum in: Nat Chem Biol. 2011 Sep;7(9):648. Nat Chem Biol. 2011;7(8):following 574. PubMed PMID: 21743462; PubMed Central PMCID: PMC3184254.