Advancing TET Inhibitor Development: From Structural Insights to Biological Evaluation
Ten-eleven translocation (TET) methylcytosine dioxygenases are part of the epigenetic regulatory machinery that erases DNA methylation. Aberrant TET activities are frequently found in hematopoietic malignancies, where loss of TET2 function leads to DNA hypermethylation. A comprehensive understanding of the biological role of TETs is essential to elucidate disease pathogenesis and identify novel therapeutic strategies. We present a robust pipeline integrating protein X-ray crystallography, molecular modeling, and pharmacophore analysis to advance the current TET inhibitor development. In addition, we have synthesized and evaluated a series of 8-hydroxyquinoline (8-HQ) derivatives, demonstrating their potential as chemical tools to explore TET function further. These findings lay the groundwork for a TET-centered therapeutic approach.
Authors
- Suzanne Willems (ORCID: https://orcid.org/0000-0001-7288-5539)
- Tom Schulz (ORCID: https://orcid.org/0000-0003-4070-7791)
- Sonja Sievers (ORCID: https://orcid.org/0000-0003-0854-4507)
- Janina Niggenaber (ORCID: https://orcid.org/0000-0003-2942-263X)
- Daniel Summerer (ORCID: https://orcid.org/0000-0002-3019-7241)
- Daniel Rauh (ORCID: https://orcid.org/0000-0002-1970-7642)
- Matthias Philipp Müller (ORCID: https://orcid.org/0000-0002-1529-8933)
- Jörn Weisner (ORCID: https://orcid.org/0000-0002-6103-7371)
- Tzu‐Chen Lin
- Lejla Maksumic
Institutions
- TU Dortmund University (DE)
- Max Planck Institute of Molecular Physiology (DE)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00042
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- European Synchrotron Radiation Facility
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe
- Mercator Research Center Ruhr
- Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
- European Regional Development Fund