A platinated prodrug leveraging PROTAC technology for targeted protein degradation and enhanced antitumor efficacy†

Proteolysis targeting chimeras (PROTACs), which catalytically degrade disease-related proteins, can overcome the limitations of traditional small-molecule inhibitors and thus have revolutionized the field of targeted therapy. Building on this advancement, we present platinated PROTAC [PROTAC–Pt(IV)], a new class of “dual-action” prodrug that leverages the ubiquitin–proteasome system-mediated degradation capabilities of PROTAC and exhibits the advantages of Pt-based anticancer prodrugs. PROTAC–Pt(IV) exhibits exceptional cytotoxicity, with half-maximal inhibitory concentration values in the nanomolar range. It outperformed conventional inhibitor-based Pt(IV) prodrugs by up to three orders of magnitude by efficiently degrading the target protein BRD4 in a range of human cancer cells. PROTAC–Pt(IV) induces cancer cell death through mechanisms including augmented apoptosis, p21-mediated cell cycle arrest, and immune activation via PD–L1 downregulation. Compared with PROTAC alone, PROTAC–Pt(IV) more effectively suppressed the growth of tumor xenografts in a mouse model via its altered pharmacokinetic properties. Collectively, the development of PROTAC–Pt(IV) marks a revolution in dual-action Pt(IV) anticancer prodrugs and offers a promising avenue for enhanced and targeted cancer therapies.