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/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 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, we thought that targeting PTK7/β-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 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 anti-proliferative effect in vitro in CRC cells harboring β-catenin or APC mutations downstream of PTK7. Thus, inhibition of the PTK7/β-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.
