Toward Drug Repurposing in Epigenetics: Olsalazine as a Hypomethylating Compound Active in a Cellular Context

DNA hypomethylating drugs that act on DNA methyltransferase (DNMT) isoforms are promising anticancer agents. By using a well‐characterized live‐cell system to measure DNA methylation revisions (imprints), we characterize olsalazine, an approved anti‐inflammatory drug, as a novel DNA hypomethylating agent. The cell‐based screen used in this work 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, with minimal cytotoxicity at the concentrations tested. Olsalazine was identified by a rapid computer‐guided similarity search of a database of approved drugs to a previously identified inhibitor of DNMTs. A bold new direction: Using a novel DNA methylation reprogramming system that operates in the context of living cells, we report the characterization of olsalazine, an anti‐inflammatory drug, as a new DNA hypomethylating agent. The results come from cell‐based assays that monitor the activity of DNA methyltransferase (DNMT) in living cells.