Inhibitory effect on the proteasome regulatory subunit, RPN11/POH1, with the use of Capzimin-PROTAC to trigger apoptosis in cancer cells

Sammanfattning: Most patients diagnosed with cancer will receive systematic chemotherapy at some point during their illness, which almost always cause severe side effects for the patients such as, anemia, nausea and vomiting. The problems with today’s chemotherapy is not only that it cause severe side effects, but also that the cancer may develop resistance to the therapy, which is why the development of a new type of therapeutic agent is in dire need. The ubiquitin proteasome system (UPS) is a vital machinery for the cancer cells to maintain protein homeostasis, which also make them vulnerable to any disruption of this system. In recent years, a new technology has been developed that utilize the UPS by chemically bringing an E3 ubiquitin ligase into close proximity of a protein of choice and tagging the protein with ubiquitin for degradation. This technology is called proteolysis targeting chimera (PROTAC). In this project, we managed to theoretically develop a new type of cancer therapeutic agent, that utilize the PROTAC system together with the first-in-class proteasome regulatory subunit, POH1, inhibitor Capzimin as a warhead. By using Capzimin as a warhead it should be possible to polyubiquitinate POH1, and thus induce proteotoxic stress in the cancer cells to trigger apoptosis. This theoretically developed drug is therefore called Capzimin-PROTAC, which should be able to trigger apoptosis in cancer cells, and at the same time being relatively safe to normal healthy cells.