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bioRxiv · 10.1101/2021.10.15.464507

Discovery of small molecule inhibitors of the PTK7/β-catenin interaction targeting the Wnt signaling pathway in colorectal cancer

Ganier, L.·Betzi, S.·Derviaux, C.·Roche, P.·Muller, C.·Hoffer, L.·Morelli, X.·Borg, J.-P.
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Abstract

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/{beta}-catenin pathway signaling, in part, through a kinase-domain dependent interaction with the {beta}-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/{beta}-catenin pathway signaling through {beta}-catenin accumulation. Thus, we thought that targeting PTK7/{beta}-catenin interaction could be of interest for future drug development. In this study, we have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and {beta}-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 anti-proliferative effect in vitro in CRC cells harboring {beta}-catenin or APC mutations downstream of PTK7. Thus, inhibition of the PTK7/{beta}-catenin interaction could represent, in the future, 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.

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Ganier, L., Betzi, S., Derviaux, C., Roche, P., Muller, C., Hoffer, L., Morelli, X., Borg, J.-P.. 2021-10-15. Discovery of small molecule inhibitors of the PTK7/β-catenin interaction targeting the Wnt signaling pathway in colorectal cancer. https://doi.org/10.1101/2021.10.15.464507

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