Once a molecule (often a protein) is implicated in disease, the drug-development process begins—and that typically means chemists designing small-molecule drugs that bind the protein and alter its activity. But some disease-related proteins are kind of slippery – they lack obvious binding pockets or have surfaces that are difficult for small molecules to engage, making them effectively “undruggable.” A newer strategy called PROTACs (or, proteolysis-targeting chimeras) offers a workaround: rather than inhibiting a protein, a PROTAC links the target to the cell’s own protein-disposal machinery (the quality-control system that removes unwanted proteins). The target is then tagged and degraded, so whether it was traditionally druggable becomes largely irrelevant.
Here, researchers from The Scripps Research Institute (La Jolla, CA) and the CeMM Research Center (Vienna) describe a faster, more systematic way to discover degrader-type drugs. They begin with small molecules already known to bind a disease-relevant target, then rapidly “decorate” these starting compounds with thousands of different chemical appendages using SuFEx click-style chemistry. The goal is to identify variants that can recruit the cell’s protein-disposal machinery—effectively acting as a “glue” that brings the target and degradation system together. Instead of laboriously purifying every new compound, the team tests the crude reaction products directly in cells for evidence of target protein degradation. Overall, this approach turns degrader discovery into a scalable search process, reducing reliance on chance and expanding the range of targets that may be reachable with PROTAC-style therapies.
