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Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/ß-catenin signaling inhibitors to suppress colorectal cancer.
Zhou, Jianhui; Xu, Beibei; Shen, Qianwen; Zhang, Zhenwei; Hu, Yuting; Wang, Mengxue; Su, Yongcheng; Lei, Ziyu; Zhang, Wenqing; Liu, Tao; Liu, Hong; Hu, Tianhui; Zhou, Yu.
Afiliación
  • Zhou J; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xu B; Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, S
  • Shen Q; Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • Zhang Z; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • Hu Y; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Wang M; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Su Y; Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • Lei Z; Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • Zhang W; Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • Liu T; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Liu H; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for
  • Hu T; Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China; Shenzhen Research Institute of Xiamen University, Shenzhen, 518057, China. Electronic address: thu@xmu.edu.cn.
  • Zhou Y; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for
Eur J Med Chem ; 276: 116664, 2024 Oct 05.
Article en En | MEDLINE | ID: mdl-39018921
ABSTRACT
Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/ß-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of ß-catenin, thereby suppressing the Wnt/ß-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/ß-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ensayos de Selección de Medicamentos Antitumorales / Neoplasias Colorrectales / Tetrahidroisoquinolinas / Proliferación Celular / Beta Catenina / Vía de Señalización Wnt / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ensayos de Selección de Medicamentos Antitumorales / Neoplasias Colorrectales / Tetrahidroisoquinolinas / Proliferación Celular / Beta Catenina / Vía de Señalización Wnt / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Francia