2. Academic Validation
  3. Discovery of the first-in-class DOT1L PROTAC degrader

Discovery of the first-in-class DOT1L PROTAC degrader

  • Eur J Med Chem. 2025 Jul 5:291:117595. doi: 10.1016/j.ejmech.2025.117595.
Hyerin Yim 1,  Renhong Sun 1,  Zhongli Xu 1,  Huen Suk Kim 1,  Minjeong Kim 1,  Tao Cao 1,  Ling Xie 2,  Xian Chen 2,  H Ümit Kaniskan 3,  Jian Jin 4
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, NY, 10029, United States.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
  • 3 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, NY, 10029, United States. Electronic address: husnu.kaniskan@mssm.edu.
  • 4 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, NY, 10029, United States. Electronic address: jian.jin@mssm.edu.
PMID: 40186895 DOI: 10.1016/j.ejmech.2025.117595
Abstract

DOT1L is the lysine methyltransferase responsible for histone H3 lysine 79 (H3K79) methylation and plays a crucial role in leukemia progression. Furthermore, DOT1L has biological functions that are independent of its methyltransferase activity. Therefore, targeting and degrading DOT1L with PROteolysis TArgeting Chimeras (PROTACs) could represent a promising therapeutic strategy. Here, we report the discovery of the first-in-class DOT1L PROTAC degrader, compound 13 (MS2133), which potently induces DOT1L degradation in a concentration- and time-dependent manner, without affecting DOT1L mRNA expression. The DOT1L degradation induced by 13 requires binding to the E3 Ligase von Hippel-Lindau (VHL) and DOT1L and occurs through the ubiquitin-proteasome system. 13 is selective for DOT1L over Other methyltransferases and effectively inhibits the growth of mixed lineage leukemia-rearranged (MLL-r) leukemia cells while having no toxicity on normal cells. Overall, 13 is a valuable chemical biology tool for further studying functions of DOT1L and a potential therapeutic for DOT1L-dependent cancers.

Keywords

DOT1L; Degrader; Leukemia; Methyltransferase; PROTAC.

Figures
Products