A proteolysis targeting chimera (PROTAC) is a heterobifunctional small molecule composed of two active domains and a linker, capable of removing specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis.

PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome.

Because PROTACs need only to bind their targets with high selectivity (rather than inhibit the target protein’s enzymatic activity), there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.

Proteolysis targeting chimera – Wikipedia

The proteolysis-targeting chimera (PROTAC) molecule consists of three components, a ubiquitin E3 ligase ligand, a linker, and a target protein ligand. PROTACs are dependent on the ubiquitin proteasome system (UPS) for degradation of target proteins.

PROTAC technology has received enormous attention for its ability to overcome the limitations of protein inhibitors and its capability to target undruggable proteins. The application of this technology is rapidly gaining momentum, especially in cancer therapy. Many companies are working in this area of emerging new modality and a few PROTACs have already entered clinical trials.