2. Academic Validation
  3. Design, synthesis and biological evaluation of quercetin derivatives as novel β-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors

Design, synthesis and biological evaluation of quercetin derivatives as novel β-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors

  • Eur J Med Chem. 2023 Feb 5:247:115075. doi: 10.1016/j.ejmech.2022.115075.
Li-An Shen 1,  Xinyan Peng 2,  Ya Bao 2,  Chenglong Liu 1,  Hao Zhang 3,  Jianqi Li 2,  Di Zhu 4,  Qingwei Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China.
  • 3 School of Pharmacy, Fudan University, Shanghai, 201203, China; Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China.
  • 4 School of Pharmacy, Fudan University, Shanghai, 201203, China; Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai, 201100, China. Electronic address: [email protected].
  • 5 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 36599228 DOI: 10.1016/j.ejmech.2022.115075
Abstract

The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in Cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on β-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with β-catenin and disrupted the β-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal Cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/β-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore β-catenin-related biology and a drug-like quercetin derivative as novel β-catenin/BCL9 PPI inhibitors for further drug development.

Keywords

Colorectal cancer; Derivatives; Protein-protein interaction; Quercetin; β-catenin/BCL9.

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