Small Molecule Inhibitors of TET Dioxygenases: Bobcat339 Activity Is Mediated by Contaminating Copper(II)

Nicholas A. Weirath, Alexander K. Hurben, Christopher Chao, Suresh S. Pujari, Tao Cheng, Shujun Liu, Natalia Y. Tretyakova

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Ten eleven translocation (TET) dioxygenases 1-3 are non-heme Fe(II) and α-ketoglutarate dependent enzymes that catalyze oxidation of 5-methylcytosine (5mC) in DNA to hydroxymethyl-C, formyl-C, and carboxy-C. This typically leads to gene activation and epigenetic remodeling. Most known inhibitors of TET are α-ketoglutarate mimics that may interfere with other α-ketoglutarate dependent enzymes. Recently, a novel cytosine-based inhibitor of TET, Bobcat339, was reported to have mid-μM inhibitory activity against TET1 and TET2. The molecule is now sold as a TET inhibitor by several vendors. We independently prepared Bobcat339 in our laboratory and observed that it had minimal inhibitory activity against human TET1 and TET2 via a quantitative LC-ESI-MS/MS assay. Furthermore, the inhibitory activity of commercial Bobcat339 preparations was directly correlated with Cu(II) content. We therefore conclude that Bobcat339 alone is not capable of inhibiting TET enzymes at the reported concentrations, and that its activity is enhanced by contaminating Cu(II).

Original languageEnglish (US)
Pages (from-to)792-798
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume13
Issue number5
DOIs
StatePublished - May 12 2022

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Institutes of Health under grant number 5R01CA095039-13.

Publisher Copyright:
© 2022 American Chemical Society.

Keywords

  • 5-Methyl-cytosine
  • Cancer
  • DNA methylation
  • Epigenetics
  • TET dioxygenase
  • TET inhibitors

PubMed: MeSH publication types

  • Journal Article

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