Cellular Morphological Profiling of PROTAC Degraders of the m6A RNA Methyltransferase METTL3
Abstract Methylation of N6-adenosine is the most abundant RNA modification, which is mainly installed on mRNA by the methyltransferase METTL3–METTL14 complex. Dysregulation of the catalytic activity of METTL3 has been associated with many human diseases, especially in acute myeloid leukemia and other cancers. Therefore, both monovalent small-molecule inhibitors and bivalent heterobifunctional proteolysis-targeting chimera (PROTAC) degraders have been pursued to address METTL3 for therapeutic development. In this study, we report the structure-based design and synthesis of new METTL3-targeting PROTACs, as well as the first application of unbiased morphological profiling of the obtained METTL3 PROTACs in the cell painting assay to obtain phenotypic characterization data for the further development of METTL3 PROTAC degraders.
Authors
- Katarzyna W. Kliza (ORCID: https://orcid.org/0000-0002-1213-1812)
- Sonja Sievers (ORCID: https://orcid.org/0000-0003-0854-4507)
- Jeffrey L. Schloßhauer (ORCID: https://orcid.org/0009-0000-2583-3445)
- Peng Wu (ORCID: https://orcid.org/0000-0002-0186-1086)
- Laura Wortmann (ORCID: https://orcid.org/0000-0002-3210-0474)
- Chukwudi Thomas UGWU
- Christian Begemann
- Mao Jiang
Institutions
- TU Dortmund University (DE)
- Max Planck Institute of Molecular Plant Physiology (DE)
- Max Planck Institute of Molecular Physiology (DE)
Publication Details
- Journal
- ACS Bio & Med Chem Au
- Published
- 2026-10-06
- DOI
- https://doi.org/10.1021/acsbiomedchemau.6c00136
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00