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Lookup NU author(s): Dr Roman Belle, Dr Hilal SaracORCiD, Dr Grace Roper, Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Ten-eleven translocation enzymes (TETs) are Fe(II)/2-oxoglutarate (2OG) oxygenases that catalyze the sequential oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in eukaryotic DNA. Despite their roles in epigenetic regulation, there is a lack of reported TET inhibitors. The extent to which 2OG oxygenase inhibitors, including clinically used inhibitors and oncometabolites, modulate DNA modifications via TETs has been unclear. Here, we report studies on human TET1–3 inhibition by a set of 2OG oxygenase-focused inhibitors, employing both enzyme-based and cellular assays. Most inhibitors manifested similar potencies for TET1–3 and caused increases in cellular 5hmC levels. (R)-2-Hydroxyglutarate, an oncometabolite elevated in isocitrate dehydrogenase mutant cancer cells, showed different degrees of inhibition, with TET1 being less potently inhibited than TET3 and TET2, potentially reflecting the proposed role of TET2 mutations in tumorigenesis. The results highlight the tractability of TETs as drug targets and provide starting points for selective inhibitor design.
Author(s): Belle R, Saraç H, Salah E, Bhushan B, Szykowska A, Roper G, Tumber A, Kriaucionis S, Burgess-Brown N, Schofield CJ, Brown T, Kawamura A
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 2024
Pages: Epub ahead of print
Online publication date: 31/01/2024
Acceptance date: 04/01/2024
Date deposited: 07/03/2024
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acs.jmedchem.3c01820
DOI: 10.1021/acs.jmedchem.3c01820
PubMed id: 38294854
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