A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression.

The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in -rearranged (-r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel-Lindau-recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms' tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.