Zebularine

Zebularine, a cytidine analog, is a DNA methylation inhibitor that acts by forming a covalent complex with DNA methyltransferases (DNMTs).¹ By stabilizing the binding of DNMTs to DNA, zebularine hinders methylation and decreases dissociation, trapping DNMT and preventing its turnover.² Zebularine preferentially targets cancer cells in various human carcinoma cell lines demonstrating IC₂₀ values of 20, 10, 20, and 5 μM for reducing proliferation of TK6, Jurkat, KG-1, and HCT116 cells, respectively.³ Zebularine exhibits low toxicity in mice even after prolonged administration (0.2 mg/ml drinking water for 113 days in a mouse intestinal cancer model).⁴

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1. Zhou, L., Cheng, X., Connolly, B.A., et al. Zebularine: A novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases. J. Mol. Biol. 321(4), 591-599 (2002).

2. Champion, C., Guianvarc'h, D., Sénamaud-Beaufort, C., et al. Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PLoS One 5(8), e12388 (2010).

3. Stresemann, C., Brueckner, B., Musch, T., et al. Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res. 66(5), 2794-2800 (2006).

4. Yoo, C.B., Chuang, J.C., Byun, H.M., et al. Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice. Cancer Prev. Res. 1(4), 233-240 (2008).