Dottorato in SCIENZE FARMACEUTICHE

Titolo della tesi: Tubulin, β-Catenin, carbonic anhydrase and Gab2 inhibitors as effective targets in anticancer therapy

During my three years as a Phd student I have worked on several projects, mostly concerning research and development of new anticancer drugs. The wider project concerned the development of new chemotherapy agent as inhibitor of tubulin polymerization. My research group has significant experience in this field, so we decided to continue this study focusing on the need to overcome problems such as drug resistance and poor bioavailability. Starting from derivatives previously reported, we made structural modification to implement pharmacodynamic and pharmacokinetic properties. The results of cell tests of these novel inhibitors showed a significant activity in many cell lines, which showed resistance to approved drug. In vivo studies have also highlighted the efficiency of some derivatives to brain tumors such as glioblastoma. Many traditional drugs, indeed, fail to effectively cross-epithelial and cellular barriers, which reduces their effectiveness and requires high dosages. These novel tubulin polymerization inhibitors have instead a better pharmacokinetic profile, proving to be able to cross the blood-brain barrier. Another goal of my PhD course was the search for new targets for cancer therapy. A widespread problem is the poor selectivity of the classic chemotherapeutic compounds, able to inhibit the proliferation of cancer cells, but showing a certain cytotoxicity also towards normal cells. Anticancer therapy is, therefore, increasingly focus on new specific cancer targets. In this context, we have developed new inhibitors of β-catenin, Gab2 and carbonic anhydrase. Finally, I took part in two small projects also in the antiviral field. Starting from docking studies, we have developed possible antiviral agents active against Norovirus or Zikavirus