A1914-10mg | UNC0638 [1255580-76-7] Clinisciences

Background

UNC0638 is a potent and selective inhibitor of G9a and GLP with IC50 values of < 15 nM and 19 ± 1 nM, respectively [1].

GLP forms a heterodimer with G9a. Both G9a and GLP can mono- and dimethylate histone H3 Lys9 (H3K9), and dimethylate Lys373 of p53 and hence inactivate the transcriptional activity of p53 [1].

UNC0638 showed balanced physicochemical properties and potency aiding cell penetration in vitro, had high potency in cellular assays. It was much less toxic than BIX01294 to cells. In MDA-MB-231 cells, in a concentration-dependent manner, exposure to UNC0638 for 48 h reduced H3K9me2 levels with an IC50 value of 81 ± 9 nM (n= 3), which showed considerably higher potency than BIX01294 (IC50= 500 ± 43 nM (n= 3)). In reducing H3K9me2 levels, UNC0638 was of greater maximum effect than BIX01294. This effect is close, but not equal, to the effect on the double knockdown of G9a and GLP via shRNA [1].

In 6-week-old male athymic nude mice subcutaneously inoculated with BON cells, UNC0638 decreased H3K9me2 level [2]. In organotypic cochlear cultures, rapid increase of H3K9me2 upon the damage of hair cells was observed. Both ex vivo and in vivo, UNC0638 effectively prevented aminoglycosides-induced hair cell damage [3].

References:
[1]. Vedadi M., Barsyte-Lovejoy D., Liu F., et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nature Chemical Biology, 2011, 7:566-574.
[2]. Kim J.T., Li J., Jang E.R., et al. Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors. Clin. Carcinogenesis, 2013, 00(00):1-9.
[3]. Yu H., Lin Q., Wang Y., et al. Inhibition of H3K9 methyltransferases G9a/GLP prevents ototoxicity and ongoing hair cell death. Cell Death and Disease, 2013, 4:e506.

Product Citation

1. Liu M, Thomas SL, et al. "Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells." Cancer Res. 2018 Oct 15;78(20):5754-5766. PMID:30185548

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	509.72
Cas No.	1255580-76-7
Formula	C₃₀H₄₇N₅O₂
Solubility	≥25.5 mg/mL in DMSO; insoluble in H2O; ≥48.2 mg/mL in EtOH
Chemical Name	2-cyclohexyl-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine
SDF	Download SDF
Canonical SMILES	CC(C)N1CCC(CC1)NC2=NC(=NC3=CC(=C(C=C32)OC)OCCCN4CCCC4)C5CCCCC5
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	MDA-MB-231 cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reaction Conditions	80, 250, 500 nM; 1 d to 4 d
Applications	In MDA-MB-231 cells, in a concentration-dependent manner, exposure to UNC0638 for 48 h reduced H3K9me2 levels with an IC50 value of 81 ± 9 nM. Cellular levels of H3K9me2 were progressively reduced from 1 d to 4 d exposure to UNC0638 at the concentrations of 80 nM (IC50), 250 nM (IC90) and 500 nM (2 × IC90). The reductions of H3K9me2 levels with 250 nM and 500 nM treatments after 4 d were equal or very close to that of G9a and GLP knockdown cells. The effects of UNC0638 were long-lasting. In cells with 2 d exposure to UNC0638, levels of H3K9me2 remained low after washout of compound followed by 2 d incubation without the inhibitor.
Animal experiment [2]:
Animal models	Swiss Albino mice
Dosage form	5 mg/kg; i.p.
Applications	UNC0638 was not suitable for animal studies due to its poor pharmacokinetic properties.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Vedadi M., Barsyte-Lovejoy D., Liu F., et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nature Chemical Biology, 2011, 7:566-574. [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 Nov 14;56(21):8931-42.

Biological Activity

Description	UNC0638 is a potent and selective inhibitor of G9a and GLP HMTase with IC50 values of < 15 nM and 19 nM, respectively.
Targets	G9a	GLP
IC50	< 15 nM	19 nM

Quality Control

Purity = 98.66%

Chemical structure

UNC0638 [1255580-76-7]

Référence A1914-10mg

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