PROTAC

A PROTAC is a clever two-headed molecule that does not block a disease protein but instead marks it for the cell's own garbage disposal. One end grabs the target protein; the other end grabs a piece of the cell's recycling machinery. By holding the two together, the PROTAC tricks the cell into tagging the target for destruction, like handcuffing a culprit to a waste-collection truck.

The recycling machinery in question is the ubiquitin–proteasome system: cells normally label worn-out proteins with a small marker called ubiquitin, and a shredder called the proteasome then chews them up. A PROTAC recruits an enzyme called an E3 ubiquitin ligase to the target, so the target gets the destruction label and is fed to the proteasome. The PROTAC itself is released and can go do it again, acting catalytically.

Because a PROTAC eliminates the whole protein rather than merely occupying its active site, it can hit targets that lack a good drug pocket and can overcome some resistance mutations. The challenges are real, though: these molecules are large, which makes oral absorption and cell entry difficult, and getting the geometry of the three-way embrace right is a demanding design problem.