Nowadays cancer is one of the most important causes of death. Chemotherapy is the therapeutic strategy that has had the highest evolution in the last years. Nevertheless, a relapse is frequently observed during therapy, due to the development of multidrug resistance. For this reason, it is essential the investigation of a new therapeutic oncological target. The present research project aims to design and synthesize new anticancer drugs targeting ß-catenin. Sulfonamide, ß-catenin inhibitors, combined with NHERF1 inhibitors are expected to inhibit colorectal cancer (CRC). A derivative bearing N-Aryl benzenesulfonamide scaffold inhibit Wnt/ ß-catenin signaling pathway with selective antitumor effect on Wnt-dependent cancer cell in vitro and in mouse models. In this research project, will be carried out a test set of compounds mainly focusing on the substituents at the ring A and the position of the ester functional group at the ring B, to outline the structure-activity relationship in this novel class of ß-catenin inhibitors.
Recently, increasing attention has been paid to cellular signal transduction in CRC, especially Wingless¿Int (Wnt) pathway which regulates cell growth, differentiation and death in embryogenesis and tumor development, attributing to the presence of an activating mutation of the canonical Wnt signaling pathway in about 90% of all CRCs. The Wnt/ß-catenin pathway is activated in more than 90% of CRCs by mutations in either the APC gene (80%-85%) or the gene encoding ß-catenin (5%-10%). The activity of ß-catenin is modulated by several highly regulated process, like ligand-receptor interactions, ß-catenin stability, ß-catenin nuclear translocation and ß-catenin transcriptional activity. This implies the requirement of further studies to determine the mechanisms that control this process, to identify pivotal signaling nodes that could be targeted by therapeutic interventions.
Another advantage of this new target, thanks to the complexity, is the possibility to use different strategies, different target in association to increase the therapeutic response. The complexity of the Wnt signaling pathway offers multiple levels of therapeutic intervention, and currently, there is a big variety of approaches aimed to reduce Wnt/ ß-catenin signaling output.
Nowadays, there are only two studies on Sulfonamide inhibitors of ß-catenin pathway, the results of which show inconsistencies. Fueled by the purpose of developing novel ß-catenin inhibitors as anticancer agent, and to provide a new SAR profile, we will develop a novel group of sulphonamide with different substituent to investigate the real influence on the inhibitory activity of the different substituents and, possibly, to find derivatives with profile of activity better than the inhibitors already known.