Discovery of a Highly Potent and Selective ENL Degrader

  • J Med Chem. 2026 May 14;69(9):11192-11228. doi: 10.1021/acs.jmedchem.6c00386.
Kaixiu Luo  1 ,  Zhaoyu Xue  2 ,  Lihuai Qin  1 ,  Zhefan Wang  2 ,  Pengcheng Gao  1 ,  Ling Xie  3 ,  Yangzhou Su  2 ,  Xian Chen  3 ,  H Ümit Kaniskan  1 ,  Hong Wen  2 ,  Jian Jin  1
Affiliations
  • 1. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, the Mount Sinai Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2. Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan 49503, United States.
  • 3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 42025203 DOI: 10.1021/acs.jmedchem.6c00386
Abstract

The eleven-nineteen leukemia protein (ENL), a YEATS domain-containing acyl-lysine reader, represents a critical dependency in acute myeloid leukemia (AML). We previously reported our first-generation ENL proteolysis-targeting chimera (PROTAC) degrader, MS41. Here, via a comprehensive structure-activity relationship (SAR) study, we discovered MS108 (compound 124), the most potent ENL degrader to date, which recruits the von Hippel-Lindau (VHL) E3 Ligase and achieved 5.8-fold higher ENL degradation potency (DC50 = 0.6 ± 0.05 nM) and 18-fold stronger antiproliferation potency (GI50 = 1.19 ± 0.03 nM) over MS41 in MV4;11 cells. Compound 124 induced robust and highly selective degradation of ENL in a concentration-, time-, VHL-, and ubiquitin-proteasome system (UPS)-dependent manner while displaying improved pharmacokinetic properties. Collectively, we discovered a highly potent and selective ENL degrader, providing a useful chemical tool for the research community and a compelling lead for further development of ENL degraders into therapeutics to treat AML.

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