Proteolysis-targeting chimeras

Proteolysis-targeting chimeras (PROTACs) are chimeric small-molecule therapeutics designed to eliminate selected intracellular proteins rather than merely inhibit their activity. A typical PROTAC contains two binding elements connected by a chemical linker: one recognizes a target protein and the other recruits an E3 ubiquitin ligase, such as cereblon (CRBN) or a von Hippel–Lindau (VHL) complex. Formation of the resulting ternary complex brings the target protein into proximity with the E3 ligase, promoting ubiquitination and subsequent destruction by the ubiquitin–proteasome system 42089481May.

Because PROTACs act through event-driven protein degradation, a single molecule can promote the removal of multiple target-protein molecules and may address proteins that are difficult to inhibit pharmacologically. This modality has consequently been investigated in cancer and other disease-oriented drug-discovery programs, including efforts to overcome drug resistance and degrade mutant EGFR. PROTAC research also addresses pharmaceutical limitations such as cellular uptake, potency, selectivity, oral bioavailability and tissue delivery. In the current literature, recurring strategies include CRBN- and VHL-recruiting degraders, prodrug design, self-assembly, liposomal delivery and combinations with other targeted-therapy approaches.