targeted protein degrader
A targeted protein degrader is a drug that does not just switch a harmful protein off but arranges for the cell to throw it away entirely. A classic inhibitor is like holding a machine's button down; a degrader is like calling the recycling truck so the machine is removed for good.
It works by hijacking the cell's own quality-control system, the ubiquitin-proteasome pathway. The degrader brings the target protein into contact with an enzyme called an E3 ubiquitin ligase, which tags the target with ubiquitin marks; the proteasome then recognizes those marks and shreds the protein. The two main designs are bifunctional molecules called PROTACs, which have a handle for the target and a handle for the ligase, and smaller molecular glues that induce the same contact.
Because the degrader is released after each protein is destroyed and can act again, it works catalytically, often at low doses. Crucially, removing the whole protein can shut down functions an inhibitor cannot, including scaffolding roles that have no active site. The trade-offs include large molecular size, difficult oral delivery, and the need for a suitable E3 ligase in the target tissue.
A PROTAC against an estrogen receptor links a binder for the receptor to a binder for an E3 ligase, so the cell ubiquitinates and degrades the receptor instead of merely blocking it.
A molecule that directs a target protein to the cell's disposal machinery.
Because degraders remove the protein entirely, they can hit targets that lack a deep druggable pocket, expanding the universe of 'druggable' proteins.