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ACS Med Chem Lett. 2019 Jan 31;10(2):180-185. doi: 10.1021/acsmedchemlett.8b00474. eCollection 2019 Feb 14.

Cytosine-Based TET Enzyme Inhibitors.

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Department of Chemistry and Biochemistry, Bates College, 2 Andrews Road, Lewiston, Maine 04240, United States.
Department of Biology and Program in Neuroscience, Bates College, 44 Campus Avenue, Lewiston, Maine 04240, United States.


DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states such as cancer. The TET family of enzymes is known to be responsible for catalyzing the reverse process that is DNA demethylation by recognizing 5-methylcytosine and oxidizing the methyl group via an Fe(II)/alpha-ketoglutarate-dependent mechanism. Here, we describe the design, synthesis, and evaluation of novel cytosine-based TET enzyme inhibitors, a class of small molecule probes previously underdeveloped but broadly desired in the field of epigenetics. We identify a promising cytosine-based lead compound, Bobcat339, that has mid-μM inhibitor activity against TET1 and TET2, but does not inhibit the DNA methyltransferase, DNMT3a. In silico modeling of the TET enzyme active site is used to rationalize the activity of Bobcat339 and other cytosine-based inhibitors. These new molecular tools will be useful to the field of epigenetics and serve as a starting point for new therapeutics that target DNA methylation and gene transcription.

[Available on 2020-02-14]

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