Discovery of a Highly Potent and Selective ENL Degrader.

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.