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 12:129591. doi: 10.1016/j.bmcl.2023.129591. Online ahead of print.ABSTRACTThe 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.PMID:38097141 | DOI:10.1016/j.bmcl.2023.129591
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Source Type: research