KEYWORD |
Area Engineering
Design and testing of novel Proteolysis-targeting chimera (PROTAC) construct for brain cancer therapy
Thesis abroad
keywords BRAIN CANCER, DRUG DESIGN, GAMMA TUBULIN, PROTAC,
Reference persons MARCO AGOSTINO DERIU, JACEK ADAM TUSZYNSKI
External reference persons Prof. Richard Fahlman, Department of Biochemistry, University of Alberta, Edmonton, Canada
Research Groups 28- biomedica
Thesis type COMPUTATIONAL
Description 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, the student will use computational methodologies to generate potential constructs involving gamma-tubulin targeting payloads, such as gatastatin derivatives, as well linker molecules of various types and sizes to connect to previously obtained ubiquitin-binding compounds. The project will be performed in collaboration with Canadian biochemist, Dr. Richard Fahlman at the University of Alberta, and an Edmonton-based company, Hermay Pharmaceuticals. Following computational design, chemical synthesis will be undertaken and experimental tests performed at the Cross Cancer Institute in Edmonton, Alberta, Canada.
Notes Assuming overseas travel is allowed, the student will be expected to spend 4-6 months in Edmonton, Canada
Deadline 15/10/2022
PROPONI LA TUA CANDIDATURA