DNA methylation status is an important epigenetic regulator of gene expression, cell identity, and cellular function. Cells are equipped with various enzymes to carefully write and erase DNA methyl marks across the genome. One such family of DNA demethylases are ten-eleven translocation dioxygenases (Tet). Tet enzymes facilitate DNA demethylation through a Fe(II)/alpha-ketoglutarate dependent oxidation of methylcytosine (mC) to hydroxymethylcytosine (hmC), formalcytosine (fC), and carboxylcytosine (caC). However, the epigenetic equilibrium between methylation and demethylation is dysregulated in many pathologies, including lung cancer, chronic lymphocytic leukemia, and lung associated inflammatory diseases, due to aberrant Tet activity. To further investigate the role of dysregulated Tet enzymes, selective and potent small molecule inhibitors are needed. Currently there is a lack of such chemical tools, thus we utilized structure-based design to construct a set of novel Tet-specific inhibitors. We implemented a bifunctional strategy to simultaneously engage the enzyme’s native substrate and cofactor binding sites. We utilized <i>in silico</i> docking results to guide our synthetic effort, where we successfully accessed an initial series of 15 potential inhibitors. These compounds Tet inhibitory activity were evaluated through a biochemical enzymatic Tet assay. The most potent molecule in our series had an IC50 value of ~ 1 µM. Additionally, this molecule lowered hmC levels in preliminary cellular assays at a concentration of 25 µM, indicating cellular inhibition of Tet. Collectively this work represents a critical first step in developing potent and selective Tet inhibitors to serve as epigenetic modulators to elucidate DNA methylation’s role in disease etiology.

Modulating DNA methylation with bifunctional ten-eleven translocation dioxygenases inhibitors

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