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Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer
- Source :
- ACS Chemical Biology, ACS Chemical Biology, 2022, 17 (5), pp.1061-1072. ⟨10.1021/acschembio.1c00826⟩
- Publication Year :
- 2022
-
Abstract
- International audience; Second cause of death due to cancer worldwide, colorectal cancer (CRC) is a major public health issue. The discovery of new therapeutic targets is thus essential. The pseudokinase PTK7 intervenes in the regulation of the Wnt/βcatenin pathway signaling, in part, through a kinase-domain dependent interaction with the β-catenin protein. PTK7 is overexpressed in CRC; an event associated with metastatic development and reduced survival of non-metastatic patient. In addition, numerous alterations have been identified in CRC inducing constitutive activation of Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus,targeting PTK7/β-catenin interaction could be of interest for future drug development. We have developed a NanoBRET TM screening assay recapitulating the interaction between PTK7 and βcatenin to identify compounds able to disrupt this protein-protein interaction. A high-throughput screening allowed us to identify small molecule inhibitors targeting the Wnt pathway signaling and inducing anti-proliferative and anti-tumor effect in vitro in CRC cells harboring β-catenin or APC mutations. Thus, inhibition of the PTK7/β-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.
- Subjects :
- Receptor Protein-Tyrosine Kinases
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
General Medicine
Biochemistry
[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
[SDV.CAN] Life Sciences [q-bio]/Cancer
Mutation
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Molecular Medicine
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Colorectal Neoplasms
Cell Adhesion Molecules
Wnt Signaling Pathway
beta Catenin
Cell Proliferation
Subjects
Details
- ISSN :
- 15548937 and 15548929
- Volume :
- 17
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- ACS chemical biology
- Accession number :
- edsair.doi.dedup.....f9c580cd45ec237bff1974a96c91e97e