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

  • Sci Adv. 2024 Aug 30;10(35):eado1432. doi: 10.1126/sciadv.ado1432.
Zhaoyu Xue  1 ,  Lihuai Qin  2 ,  Hongwen Xuan  1 ,  Kaixiu Luo  2 ,  Mengying Huang  1 ,  Ling Xie  3 ,  Yangzhou Su  1 ,  Longxia Xu  1 ,  Josiah Harsh  1 ,  Brandon Dale  2 ,  Xiaobing Shi  1 ,  Xian Chen  3 ,  H Ümit Kaniskan  2 ,  Jian Jin  2 ,  Hong Wen  1
Affiliations
  • 1. Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
  • 2. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences, and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, New York, USA.
  • 3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
PMID: 39196923 DOI: 10.1126/sciadv.ado1432
Abstract

The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in mixed-lineage leukemia-rearranged (MLL-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 MLL-r 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.

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