Pt(IV)-PROTAC Complexes with Synergistic Antitumor Activity and Enhanced Membrane Permeability

A class of Pt(IV)-PROTAC complexes was designed and synthesized with dual aims of inducing DNA strand damage and inhibiting DNA repair. These complexes showed good antiproliferative activity against a range of cancer cell lines. Enhanced intracellular uptake of platinum and PROTAC was observed. Multiple mechanisms of action were identified, including the induction of DNA damage, disruption of DNA repair, and activation of mitochondrial-dependent apoptosis. One of the Pt(IV)-PROTACs, CW-2, showed excellent antitumor activity in a xenograft mouse model. These results suggest that Pt(IV)-PROTAC represents a promising strategy for the development of novel antitumor therapeutics.