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A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo.
Bai, Longchuan; Zhou, Haibin; Xu, Renqi; Zhao, Yujun; Chinnaswamy, Krishnapriya; McEachern, Donna; Chen, Jianyong; Yang, Chao-Yie; Liu, Zhaomin; Wang, Mi; Liu, Liu; Jiang, Hui; Wen, Bo; Kumar, Praveen; Meagher, Jennifer L; Sun, Duxin; Stuckey, Jeanne A; Wang, Shaomeng.
Afiliação
  • Bai L; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Zhou H; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Xu R; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Zhao Y; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Chinnaswamy K; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • McEachern D; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Chen J; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Yang CY; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Liu Z; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wang M; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Liu L; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Jiang H; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wen B; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kumar P; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
  • Meagher JL; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • Sun D; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
  • Stuckey JA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wang S; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor
Cancer Cell ; 36(5): 498-511.e17, 2019 11 11.
Article em En | MEDLINE | ID: mdl-31715132
ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Linfoma Anaplásico de Células Grandes / Fator de Transcrição STAT3 / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Cell Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Linfoma Anaplásico de Células Grandes / Fator de Transcrição STAT3 / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Cell Ano de publicação: 2019 Tipo de documento: Article