Discovery of a Highly Potent and Selective ENL Degrader
Kaixiu Luo·Jian Jin·Lihuai Qin·Zhefan Wang·Pengcheng Gao·Ling Xie·Yangzhou Su·X R Chen·H. Ümit Kaniskan·Hong Wen·Zhaoyu Xue
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 <b>124</b>), the most potent ENL degrader to date, which recruits the von Hippel-Lindau (VHL) E3 ligase and achieved 5.8-fold higher ENL deg