DNA methylation status is an important epigenetic regulator of gene expression, cell identity, and cellular function. Cells are equipped with various enzymes to carefully introduce and erase DNA methylation marks across the genome. Specifically, DNA methyltransferases (DNMT) catalyze the modification of cytosine (C) nucleobases to 5-methylcytosine (5-mC) within gene promoter regions. Conversely, a family of ten-eleven translocation dioxygenases (TET) initiate DNA demethylation per Fe(II)/alpha-ketoglutarate dependent oxidation of 5-mC. 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 DNMT and TET activity. To investigate the role of dysregulated TET enzymes in diseases, selective and potent small molecule inhibitors of TET proteins are needed. Currently there is a lack of such chemical tools, thus our research group utilized structure-based design to construct a set of novel TET-specific inhibitors. We implemented a bifunctional strategy to simultaneously engage the enzyme’s substrate and cofactor binding sites. We utilized <i>in silico</i> molecular docking results to guide our synthetic effort, where we successfully accessed an initial series of 15 potential inhibitors. These compounds were evaluated as TET inhibitors through a biochemical TET activity assay. The most potent molecule in our series had an IC<sub>50</sub> value of ~1 µM. Additionally, this molecule lowered 5-hydroxymethylcytosine (5-hmC) levels in preliminary cellular assays at a concentration of 25 µM, indicating the potential of these class of molecules to inhibit TET proteins in cells. Collectively, this work represents a critical first step in developing potent and selective TET inhibitors to serve as epigenetic modulators to elucidate the role of DNA methylation in human diseases.

Modulating DNA methylation with bifunctional ten-eleven translocation dioxygenases inhibitors

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