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A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression.
Xue, Zhaoyu; Qin, Lihuai; Xuan, Hongwen; Luo, Kaixiu; Huang, Mengying; Xie, Ling; Su, Yangzhou; Xu, Longxia; Harsh, Josiah; Dale, Brandon; Shi, Xiaobing; Chen, Xian; Kaniskan, H Ümit; Jin, Jian; Wen, Hong.
Afiliação
  • 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.
Sci Adv ; 10(35): eado1432, 2024 Aug 30.
Article em En | MEDLINE | ID: mdl-39196923
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia / Progressão da Doença Limite: Animals / Humans Idioma: En Revista: Sci Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia / Progressão da Doença Limite: Animals / Humans Idioma: En Revista: Sci Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos