Design and testing of novel Proteolysis-targeting chimera (PROTAC) construct for brain cancer therapy

Malignant tumors are some of the most serious diseases affecting human health, which clinical prognosis remains relatively poor. Therefore, there have been intensive efforts in the past years directed at the discovery and the development of new small molecules, which are in most cases natural compounds, capable of interfering with tubulin polymerization and therefore leading to their anticancer potential. In facts, microtubules are involved in various cellular processes such as cell division, cell motility and intracellular transport. Their essential role in cell division makes them a fundamental target for designing anti-mitotic agents. Microtubules are composed of αβ tubulin subunits that consist of various isotypes encoded by specific genes which are expressed in a tissue-specific manner. Tubulin isotypes regulate microtubule dynamic instability, contributing to the development of drug resistance in certain types of cancers. Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. In this project, computational methodologies have been used to generate potential constructs involving αβ tubulin dimers targeting payloads, such as combretastatin and colchicine derivatives and experimental compounds, as well as linker molecules of various types and sizes to connect to previously obtained ubiquitin-binding compounds.