Biochem/physiol Actions

Reversible: yes

Primary TargetEZH2

Cell permeable: yes

General description

A cell-permeable compound that is shown (at 1 µM concentrations) to inhibit EZH2-mediated trimethylation of K27 on histone H3 and induces the expression of cell-cycle regulatory genes, p21 and p27, as well as the cell death regulator, FBXO32, in OCI-AML3 and HL-60 cells, whereby treatment with inhibitor increases p16 levels in the former, but not the latter of the two cultures. At concentrations between 200 nm and 2000 nM, this compound is found to dose-dependently deplete the expression of polycomb group proteins EZH2, SUZ12, and EED in cultured and primary AML cell extracts. At concentrations up to ≥ 1000 nM, DZNep dose-dependently increases the percentage of apoptotic cells up to > ~ 38%, with greater potency against OCI-AML3 than HL-60 cultures and inhibits colony growth up to > ~ 85% for both cell lines. In OCI-AML3 cultures, 1000 nM of treatment demonstrates a significant increase in the accumulation of cells in the G₀/G₁ phase (58.5%) with a concomitant decrease in the number of cells in S phase (35.2%) and G₂/M phases (6.3%) of the cell cycle. When co-treated with panobinostat (PS), 200 nM to 1000nM DZNep is shown to decrease cell viability in OCI-AML3 and HL-60 cultures more effectively than DZNep alone, in a dose-dependent manner. DZNep (1mg/kg, twice per week, i.p.) and PS significantly prolong the survival of mice implanted with HL-60 cells compared to treatment with either compound alone. DZNep is also a known S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Sun, F., et al. 2009. Mol. Cancer Ther.8, 3191.Miranda, T.B., et al. 2009. Mol. Cancer Ther.8, 1579.Fiscus, W., et al. 2009. Blood13, 2733.Tan, J., et al. 2007. Genes Dev.21, 1050.Chiang, P.K., et al. 1992. J. Biol. Chem.267, 4988.Tseng, C.K., et al. 1989. J. Med. Chem.32, 1442.Glazer, R.I., et al. 1986. Biochem. Biophys. Res. Commun.135, 688.

Packaging

Packaged under inert gas

1 mg in Glass bottle

Physical form

A 25 mM (1 mg/98 µL) sterile-filtered solution of Histone Methyltransferase EZH2 Inhibitor, DZNep (Cat. No. 252790) in H₂O.

Reconstitution

Following initial thaw, aliquot and freeze (-20°C). Aliquots are stable for up to 6 monthst at -20°C.

Warning

Toxicity: Standard Handling (A)