Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors

Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues. Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its involvement in the homeostasis of many tissue types. It is well known that metal complexes, e.g. of copper(II), zinc(II), nickel(II) and platinum(II) ions, may exhibit in vitro anti-proliferative activity against different human cancer cell lines. Usually, their cytotoxic activity has been related to their binding capabilities toward biological macromolecules. In this thesis, the recently reported in vitro anticancer properties of copper(II) compounds, coupled to the known Cu2+ ! Cu+ redox activity, have been exploited to design and synthesize, new compounds as specific inhibitors of FGFR targets. The ligands were designed on the basis of the crystal structures of FGFR1 and FGFR4 co-crystallized with their known inhibitor Ponatinib. It is worth mentioning that the onset of drug resistance to of Ponatinib has been associated to its low water solubility, which partially hinders cell membrane permeability and release to the cytosol and also increases its accumulations in lipid compartments like adiposomes. For this reason, in the following thesis work, an attempt has been taken to design, synthesize and test new ligands with structural similarity to Ponatinib, as well as their positively charged derivatives, as a consequence of their coordination to cationic metal ions such as Cu2+. The anti-proliferative activity of the most promising molecules was evaluated in vitro and in vivo, in order to understand their possible mechanism of action. In details, 22 ligands and 3 copper(II) complexes have been synthesized as potential drugs against FGFR targets. In particular, the copper complexes were identified to act as pro-drugs that are spontaneously activated by hypoxia. After a screening of several tumor cell lines to test the activity of the newly synthesized drug candidates, lung cancer and brain tumor turned out to be the most sensitive cancer types. This study shows that the most active drugs are able to inhibit the FGF/FGFR axis efficiently.