Faculty, Staff and Student Publications
Language
English
Publication Date
2-13-2025
Journal
Journal of Medicinal Chemistry
DOI
10.1021/acs.jmedchem.4c02161
PMID
39905966
PMCID
PMC11932022
PubMedCentral® Posted Date
2-13-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
DNA methyltransferase 1 (DNMT1), which catalyzes maintenance methylation of hemimethylated DNA during DNA replication, is overexpressed in cancer. Recently, the first-in-class DNMT1-selective noncovalent small-molecule inhibitors, GSK3484862 and GSK3685032, were discovered. These inhibitors were also reported to degrade DNMT1. However, structure–activity relationship (SAR) studies of these monovalent DNMT1 degraders are lacking. Here, we report our SAR studies of this scaffold on degrading DNMT1, which led to the discovery of multiple lead degraders, including compound 4 (MS9024). Compound 4 potently and selectively degraded DNMT1 in multiple cancer cell lines in a concentration-, time-, and proteasome-dependent manner without altering DNMT1 transcription. Further mechanism-of-action studies suggest that the DNMT1 degradation induced by 4 was not mediated by lysosome or cullin RING E3 ligases but could potentially be mediated by HECT E3 ligases and/or UHRF1. Collectively, these studies pave the way for further developing DNMT1 monovalent degraders as potential therapeutics and useful chemical tools.
Keywords
Humans, DNA (Cytosine-5-)-Methyltransferase 1, Structure-Activity Relationship, Cell Line, Tumor, Enzyme Inhibitors, Proteolysis, Antineoplastic Agents, Ubiquitin-Protein Ligases
Published Open-Access
yes
Recommended Citation
Qian, Chao; Lee, Youngeun; Han, Yulin; et al., "Structure-Activity Relationship Studies of DNA Methyltransferase 1 Monovalent Degraders" (2025). Faculty, Staff and Student Publications. 5482.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5482
Graphical Abstract
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Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons