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Focused Screening Identifies Different Sensitivities of Human TET Oxygenases to the Oncometabolite 2-Hydroxyglutarate

Lookup NU author(s): Dr Roman Belle, Dr Hilal SaracORCiD, Dr Grace Roper, Professor Akane Kawamura

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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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Funding

Funder referenceFunder name
Cancer Research UKC5255/A18085
CancerResearch UK [C8717/A28285)
EP/M50659X/1
European Union’s Horizon 2020 research and innovation program [679479, 101003111)
Ludwig Cancer Research
NationalInstitute for Health Research (NIHR)
Oxford Biomedical Research Centre (BRC)
Wellcome Trust [106244/Z/14/Z]

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