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

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.