2. Academic Validation
  3. Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/β-catenin signaling inhibitors to suppress colorectal cancer

Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/β-catenin signaling inhibitors to suppress colorectal cancer

  • Eur J Med Chem. 2024 Oct 5:276:116664. doi: 10.1016/j.ejmech.2024.116664.
Jianhui Zhou 1,  Beibei Xu 2,  Qianwen Shen 3,  Zhenwei Zhang 4,  Yuting Hu 1,  Mengxue Wang 1,  Yongcheng Su 3,  Ziyu Lei 3,  Wenqing Zhang 3,  Tao Liu 5,  Hong Liu 6,  Tianhui Hu 7,  Yu Zhou 8
Affiliations

Affiliations

  • 1 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.
  • 2 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, Shenzhen, 518055, China.
  • 3 Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • 4 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.
  • 5 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 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 Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: [email protected].
  • 7 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: [email protected].
  • 8 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 Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: [email protected].
PMID: 39018921 DOI: 10.1016/j.ejmech.2024.116664
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/β-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 β-catenin, thereby suppressing the Wnt/β-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/β-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Keywords

Colorectal cancer; Hsp90; Tetrahydroisoquinoline; Wnt/β-catenin.

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