Russomanno, Pasquale (2021) Design of Small Molecules with Antitumor Activity through Computational Methodologies. [Tesi di dottorato]

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Abstract

Today, there are multiple targeted therapies against cancer. The most relevant ones are those aimed at the stop of cancer cells from growing, or at the halting of signals that stimulate blood vessels, or at helping the immune system destroy cancer cells, and many others. The last one, has achieved impressive results to date. Indeed, the immuno- oncology field is entering a new, exciting phase having the potential to change the current cancer treatment either as a standalone therapy or in combination. Recently, many innovative strategies exist to overcome tumor-induced immunosuppression. Currently the main ones are checkpoint blockade inhibitors, adoptive T cell transfers, and vaccination strategies. To date, the immuno-oncology therapeutics on the market are mostly biologic products (e.g. monoclonal antibodies (mAbs), proteins, engineered cells, and oncolytic viruses). However, for example, antibodies have specific drawbacks: high production costs, lack of oral bioavailability, poor tumor penetrating capacity, Fc-related toxicities, and immunogenic properties. In this perspective, small molecules could potentially overcome many of these issues and be complementary to, and potentially synergistic with, biologic therapeutics too. In this context, my PhD work was focused on discovery of small molecules targeting three different proteins: MDM2 (Mouse Double Minute 2) the PD-1/PD-L1 axis (Programmed cell Death protein-1/ Programmed Death-ligand 1), and STING protein (STimulator of INterferon Genes). For all targets, a tandem approach of computational studies/NMR spectroscopy was applied.

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