Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction
| Autor: | Derek R. Duckett, Zhen Wang, Vincent C. Luca, Haitao Ji, Sylvia M Frydman, Min Zhang, Victor Quereda, Qianqian Ming |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Antineoplastic Agents Mice SCID Article Metastasis Structure-Activity Relationship Piperidines BCL9 Cell Movement Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans B-cell lymphoma beta Catenin Molecular Structure Chemistry Wnt signaling pathway Cancer medicine.disease Xenograft Model Antitumor Assays Small molecule Mice Inbred C57BL Drug Design Catenin Cancer cell Cancer research Molecular Medicine Female Protein Binding Transcription Factors |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that binds with β-catenin and selectively disrupts the protein–protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development. |
| Databáze: | OpenAIRE |
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