Platinum (Pt)-based drugs such as cisplatin, carboplatin and oxaliplatin play a very important and well-documented role in treating cancer and are employed in nearly 50% of all anticancer treatments. The primary mechanism of Pt-based drugs is associated with their ability to cross-link nuclear DNA; the Pt-DNA adducts interrupt transcription, generate DNA perturbation damage responses and ultimately induce apoptosis. Pt(II) anticancer drugs also interact with a range of other nucleophiles, including RNA, mitochondrial DNA and proteins. Of these, the role Pt protein binding plays in on- and off-target activity of Pt-based drugs has been of particular interest.[1]
Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that can hijack the ubiquitin proteasome system (UPS) to achieve targeted degradation of proteins of interest.[2] Our group recently reported the first example of a metallo-PROTAC that could successfully degrade known Pt-binding proteins.[3]
PROTAC activity can be fine-tuned through the selection of linker length and type and selection of E3 ligase ligand. A novel series of PEG-based Pt PROTACs will be reported together with results to date concerning their in vitro cytotoxicity and protein degradation activity as determined by Western Blot.