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

Autor: Xue Z; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Qin L; 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., Xuan H; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Luo K; 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., Huang M; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Xie L; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Su Y; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Xu L; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Harsh J; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Dale B; 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., Shi X; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA., Chen X; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Kaniskan HÜ; 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., Jin J; 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., Wen H; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Aug 30; Vol. 10 (35), pp. eado1432. Date of Electronic Publication: 2024 Aug 28.
DOI: 10.1126/sciadv.ado1432
Abstrakt: 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.
Databáze: MEDLINE