Inhibition of FGFR and EGFR signalling by ligand traps and kinase inhibitors for anti-cancer drug discovery

Receptor protein kinases are responsible for the transduction and amplification of several growth factors which regulates the cell survival and proliferation. The deregulation of this intracellular signalling is recognized as a mechanism of cancer development, and thus growth factors and their receptors represent pharmacological targets for anti-proliferative therapies. This work describes two different approaches aimed to inhibit the intracellular signalling triggered by FGFR (fibroblast growth factor receptor) and EGFR (epidermal growth factor receptor). In case of FGFR we have investigated the structure-activity relationships of a steroidal compound called NSC12. This small-molecule belongs to a class of compounds able to prevent FGFR signalling by sequestering its extracellular ligand (FGF). Thus we synthesized a panel of non-steroidal derivatives and we evaluated their biological profile to determine how chemical modifications affect the anti-proliferative activity. In case of EGFR the research work was focused on the synthesis of kinase inhibitors targeting resistant EGFR isoforms. Here is described the design of novel compounds aimed to target a conserved lysine residue within the ATP-binding pocket, by exploiting different chemotypes as potential electrophilic groups. Finally, the last chapter of this thesis describes the design and the synthesis of Keap1-Nrf2 protein-protein interaction inhibitors as potential agents for the treatment of neurodegenerative diseases.