PROTACbased

PROTAC-based approaches refer to the use of proteolysis-targeting chimeras, heterobifunctional small molecules that recruit an intracellular E3 ubiquitin ligase to a target protein to trigger its ubiquitination and subsequent degradation by the proteasome. A PROTAC typically comprises three parts: a ligand that binds the target protein, a ligand that recruits an E3 ligase, and a chemical linker joining the two ligands. By bringing the target and an E3 ligase into proximity, the PROTAC promotes formation of a ternary complex and ubiquitination of the target, enabling sub-stoichiometric, catalytic turnover of the protein.

Design choices include selection of the E3 ligase (for example VHL or CRBN), the target-binding moiety, linker length and flexibility, and the orientation that favors productive ternary complex formation and cooperativity. The ability to degrade rather than merely inhibit the target offers access to proteins previously deemed undruggable, such as some transcription factors. PROTACs are typically small molecules but can be larger than traditional inhibitors; their physicochemical properties influence cell permeability, tissue distribution, and pharmacokinetics.

In research and development, PROTAC-based strategies are explored across oncology and other disease areas, with several candidates advancing into preclinical and early clinical trials. Targets studied include oncogenic kinases, hormone receptors, and other disease-associated proteins, with ongoing work to optimize selectivity, dosing strategies, and safety.

Challenges include achieving favorable pharmacokinetic properties, avoiding off-target degradation and resistance mechanisms, and ensuring safety in humans. The field distinguishes PROTAC-based approaches from molecular glues, which induce degradation without a bifunctional scaffold. As understanding of ternary complex formation and cooperativity improves, PROTACs may broaden therapeutic options.