Ten-eleven translocation (TET) enzymes mediate the de-methylation of DNA, an epigenetic biochemical mechanism that regulates long-term gene expression patterns, cell identity, and cellular plasticity. TET enzymes catalyze the benzylic oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, the rate-limiting enzymatic step in a process that yields an unsubstituted cytosine nucleotide in DNA. Here, we present the design, synthesis, and evaluation of Bobcat339, the lead molecule in a new class of cytosine-based TET enzyme inhibitors. We demonstrate the efficacy of Bobcat339 to decrease the production of 5-hydroxymethylcytosine in mouse hippocampal neurons, causing the buildup of methylated DNA. We then perform whole genome bisulfite sequencing to determine the precise genomic locations with increased 5-methylcytosine methylation induced by treatment of Bobcat339.

TET Inhibitor Bobcat339 increases DNA methylation in neurons

ACS Spring 2022

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