Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer.

Autor:	Ganier L; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labellisée Ligue 'Cell Polarity, Cell Signaling and Cancer', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France.; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Team 'Integrative Structural and Chemical Biology', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Betzi S; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Team 'Integrative Structural and Chemical Biology', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France.; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 'HiTS/IPCdd─High Throughput Screening Platform', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Derviaux C; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 'HiTS/IPCdd─High Throughput Screening Platform', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Roche P; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Team 'Integrative Structural and Chemical Biology', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France.; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 'HiTS/IPCdd─High Throughput Screening Platform', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Dessaux C; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labellisée Ligue 'Cell Polarity, Cell Signaling and Cancer', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Muller C; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 'HiTS/IPCdd─High Throughput Screening Platform', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Hoffer L; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Team 'Integrative Structural and Chemical Biology', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Morelli X; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Team 'Integrative Structural and Chemical Biology', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France.; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 'HiTS/IPCdd─High Throughput Screening Platform', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France., Borg JP; Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labellisée Ligue 'Cell Polarity, Cell Signaling and Cancer', 27 Blvd Lei Roure CS30059, 13273 Marseille Cedex 9, France.; Institut Universitaire de France, 17 Rue de France, 69100 Villeurbanne, France.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2022 May 20; Vol. 17 (5), pp. 1061-1072. Date of Electronic Publication: 2022 Apr 28.
DOI:	10.1021/acschembio.1c00826
Abstrakt:	Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin 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 nonmetastatic patients. In addition, numerous alterations have been identified in CRC inducing constitutive activation of the Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus, targeting the PTK7/β-catenin interaction could be of interest for future drug development. We have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and β-catenin 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 antiproliferative and antitumor effects in vitro in CRC cells harboring β-catenin or adenomatous polyposis coli (APC) mutations. Thus, inhibition of the PTK7/β-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on the 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.
Databáze:	MEDLINE
Externí odkaz: