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Published on: November 9, 2020
Discovery of a Highly Potent and Selective ENL Degrader
Kaixiu Luo1, Zhaoyu Xue2, Lihuai Qin1
1Mount 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.
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.
