2. Academic Validation
  3. Focused Screening Identifies Different Sensitivities of Human TET Oxygenases to the Oncometabolite 2-Hydroxyglutarate

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

  • J Med Chem. 2024 Jan 31. doi: 10.1021/acs.jmedchem.3c01820.
Roman Belle 1 2,  Hilal Saraç 1 2 3,  Eidarus Salah 1 4,  Bhaskar Bhushan 1 3,  Aleksandra Szykowska 4,  Grace Roper 1 2,  Anthony Tumber 1 5,  Skirmantas Kriaucionis 6,  Nicola Burgess-Brown 4,  Christopher J Schofield 1 5,  Tom Brown 1,  Akane Kawamura 1 2 3
Affiliations

Affiliations

  • 1 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, United Kingdom.
  • 2 Chemistry - School of Natural and Environmental Sciences, Bedson Building, Newcastle University, NE1 7RU Newcastle upon Tyne, United Kingdom.
  • 3 Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, OX3 7BN Oxford, United Kingdom.
  • 4 Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, OX3 7DQ Oxford, United Kingdom.
  • 5 Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, United Kingdom.
  • 6 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, OX3 7DQ Oxford, United Kingdom.
PMID: 38294854 DOI: 10.1021/acs.jmedchem.3c01820
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.

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