A proteolysis targeting chimera (PROTAC) is a small molecule composed of two active domain-binding molecules and a linker capable of removing specific unwanted proteins. one domain-binding molecule 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 by 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.
A molecular glue is a type of small-molecule drug that induces or stabilizes novel interactions between two proteins that would not normally interact. molecular glues act as an "event-driven" matchmaker. They modify the surface of one protein to create a "neosurface" that perfectly fits a target protein, essentially locking them together.
The primary clinical application for molecular glues is Targeted Protein Degradation (TPD), where they are used to eliminate disease-causing proteins that have historically been considered "undruggable". Unlike traditional inhibitors that must tightly bind inside deep, hard-to-reach pockets of a protein to block its active site, molecular glues bypass the need for an active site entirely. The monovalent molecular glue binds to a specific cellular recycling machine known as an E3 ubiquitin ligase