Notch signaling is an intercellular communication system coordinating developmental and homeostatic key processes in multiple tissue types. Perturbations in this pathway have been linked to pathogenesis and chemoresistance of multiple tumors, making its targeting one of the most promising anti-cancer therapeutic strategies. However, current Notch-interfering approaches under evaluation in clinical trials show drawbacks that limit their therapeutic use. Among the four Notch receptors (Notch1-4), inappropriate Notch3 signaling has been associated with the pathogenesis, poor prognosis and chemoresistance in specific subtypes of cancers, thus providing the rationale to develop novel Notch3 targeting-based therapies in such tumors. The aim of our proposal is to identify more effective novel Notch3-inhibitors with reduced associated toxicities with respect to the available therapeutic agents against Notch3-driven cancers. Our hypothesis is that small molecules docking within the Negative Regulatory Region (NRR) of Notch3 could stabilize the receptor in an auto-inhibited conformational status and provide signaling inhibition. Therefore, a library of natural products will be screened by molecular docking simulations against the computational structural model of the Notch3 NRR and the effectiveness of the most promising virtual hits will be investigated by assessing their strength in impairing Notch3 signaling and tumor growth in Notch3-dependent tumor contexts. Most promising compounds will be further optimized in terms of potency and specificity of action by recalling the computational modeling strategy, and structure-activity relationships will be afforded. The expected outcomes from this research proposal would provide the breakthrough in the design of novel single or combinatorial treatment of Notch3-addicted cancers.
