2. Academic Validation
  3. Structure-Activity Relationship Studies of DNA Methyltransferase 1 Monovalent Degraders

Structure-Activity Relationship Studies of DNA Methyltransferase 1 Monovalent Degraders

  • J Med Chem. 2025 Feb 13;68(3):2903-2919. doi: 10.1021/acs.jmedchem.4c02161.
Chao Qian 1,  Youngeun Lee 1,  Yulin Han 1,  Yue Zhong 1,  Jujun Zhou 2,  Joel Hrit 3,  Ling Xie 4,  Qin Chen 2,  H Ümit Kaniskan 1,  Xian Chen 4,  Scott Rothbart 3,  Xiaodong Cheng 2,  Yan Xiong 1,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2 Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 3 Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan 49503, United States.
  • 4 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 39905966 DOI: 10.1021/acs.jmedchem.4c02161
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.

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