2. Academic Validation
  3. Structure-activity relationship explorations of 2-(isoxazol-5-yl)phenyl-3,4-dihydroxybenzoate derivatives to develop potent Wnt/β-catenin pathway inhibitors for colorectal cancer treatment

Structure-activity relationship explorations of 2-(isoxazol-5-yl)phenyl-3,4-dihydroxybenzoate derivatives to develop potent Wnt/β-catenin pathway inhibitors for colorectal cancer treatment

  • Bioorg Chem. 2025 Jun 15:160:108433. doi: 10.1016/j.bioorg.2025.108433.
Li Dong 1,  Tiemei Long 2,  Shanghui Zhang 2,  Yongqing Mao 2,  Mingji Liu 3,  Fuhui Zhao 2,  Zhangxiang Yang 2,  Lei Li 4,  Shi-Wu Chen 5,  Shanggao Liao 6,  Yongxi Dong 7
Affiliations

Affiliations

  • 1 University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province & School of Pharmacy, Guizhou Medical University, Guian New District, 561113, China. Electronic address: dongli@gmc.edu.cn.
  • 2 University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province & School of Pharmacy, Guizhou Medical University, Guian New District, 561113, China.
  • 3 Pharmacy Department, Guizhou Provincial People's Hospital, Nanming District, 550002, Guiyang, China.
  • 4 Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China.
  • 5 School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
  • 6 University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province & School of Pharmacy, Guizhou Medical University, Guian New District, 561113, China. Electronic address: sgliao@gmc.edu.cn.
  • 7 University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province & School of Pharmacy, Guizhou Medical University, Guian New District, 561113, China. Electronic address: dongyongxi@gmc.edu.cn.
PMID: 40188614 DOI: 10.1016/j.bioorg.2025.108433
Abstract

In the canonical Wnt/β-catenin pathway, the nucleus translocation of β-catenin and β-catenin/ B-cell lymphoma 9 (BCL9) protein-protein interactions (PPI) promote the expressions of oncoproteins (Cyclin D1 and c-Myc), thereby inducing the colorectal Cancer. Herein, we report the identification of the highly potent Wnt/β-catenin pathway inhibitor 19 t following structure-activity relationship (SAR) exploration of 2-(isoxazol-5-yl)phenyl-3,4-dihydroxybenzoate which was discovered by our previous work. Further mechanism research confirmed that the optimized compound 19 t reduced the expressions of oncoproteins (Cyclin D1 and c-Myc) through inhibiting the nucleus translocation of β-catenin and disrupting the interaction of β-catenin/BCL9, thereby inducing the Apoptosis of SW480 cells. Encouragingly, the results of HCT116-xenograft nude mice demonstrated that the compound 19 t with acceptable pharmacokinetic parameters significantly inhibited tumor growth (TGI: 61.85 % at 20 mg/kg and 77.52 % at 40 mg/kg) and did not exhibit objective hepatotoxicity and nephrotoxicity. Consistently, the compound 19 t could also inhibit expressions of Cyclin D1 and c-Myc in vivo. Collectively, the optimized compound 19 t could serve as a promising Wnt/β-catenin pathway inhibitor for colorectal Cancer treatment.

Keywords

Colorectal cancer; Nucleus translocation; Protein-protein interactions; Structure-activity relationship; Wnt/β-catenin pathway.

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