2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the β‑catenin/B-cell lymphoma 9 interaction

Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the β‑catenin/B-cell lymphoma 9 interaction

  • Bioorg Med Chem Lett. 2023 Dec 13:98:129591. doi: 10.1016/j.bmcl.2023.129591.
Xinyan Peng 1,  Li-An Shen 2,  Ya Bao 3,  Chenglong Liu 2,  Qiushi Chen 3,  Hao Zhang 4,  Jiayi Li 5,  Qingwei Zhang 6
Affiliations

Affiliations

  • 1 Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200123, China; Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
  • 2 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3 Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
  • 4 Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry, Shanghai 201203, China; School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 5 Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry, Shanghai 201203, China; School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China.
  • 6 Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry, Shanghai 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd. Shanghai 201203, China. Electronic address: [email protected].
PMID: 38097141 DOI: 10.1016/j.bmcl.2023.129591
Abstract

The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for aberrantly active Wnt/β-catenin signaling which actively participates in initiating and progressing of many cancers. Herein, we discovered novel 8-substituted quercetin derivatives with potential inhibitory activities targeting β-catenin/BCL9 PPI. Among all the derivatives, compound B4 displayed the most promising PPI inhibitory activity with an IC50 value of 2.25 μM in a competitive fluorescence polarization assay and a KD value of 1.44 μM for the β-catenin protein. Furthermore, B4 selectively inhibited the growth of colorectal Cancer (CRC) cells, suppressed the transactivation of Wnt signaling, and downregulated the expression of oncogenic Wnt target gene. Especially, B4 showed potent anti-CRC activity in vivo with the tumor growth inhibition (TGI) of 75.99 % and regulated the tumor immune microenvironment.

Keywords

Colorectal cancer; Derivatives; Quercetin; β-catenin/BCL9 PPI.

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