DNA hypomethylating drugs that inhibit DNA methyltransferases (DNMTs) are promising compounds for the treatment of cancer and other diseases. Herein, we describe the characterization of olsalazine, an approved anti-inflammatory drug, as a novel DNA hypomethylating agent [1]. Olsalazine was identified by a fast computer-guided similarity searching of DrugBank, a database of approved drugs to a previously identified inhibitor of DNMTs [2]. In order to examine the ability of olsalazine to inhibit DNMT activity, we utilized a novel DNA methylation re-programming system that operates in the context of living cells [3]. The cell based screen used in this study is highly tractable, internally controlled and well-suited for a drug repurposing strategy in epigenetics. Olsalazine very closely mimics the action of 5-aza-2'-deoxycytidine, a known hypomethylating drug used in the clinic for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), with minimal cytotoxicity at the concentrations tested. Based on this proof of concept, a more systematic study of the similarity relationships of approved drugs to known epigenetic agents had been undertaken, and will assess the significance of these compounds to MDS and AML.[1] Mendez-Lucio, O. et al. ChemMedChem, 2014, 9, 560. [2] Kuck, D. et al. Bioorg. Med. Chem. 2010, 18, 822 [3] Morano, A. et al. Nucl. Acids Res., 2014, 42, 804.

Drug repurposing and epigenetics: Olsalazine is a hypomethylating compound active in a cellular context

248th National Meeting (2014)

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