Megan Scudellari in Nature:
When Craig Crews first managed to make proteins disappear on command with a bizarre new compound, the biochemist says that he considered it a “parlour trick”, a “cute chemical curiosity”. Today, that cute trick is driving billions of US dollars in investment from pharmaceutical companies such as Roche, Pfizer, Merck, Novartis and GlaxoSmithKline. “I think you can infer that pretty much every company has programmes in this area,” says Raymond Deshaies, senior vice-president of global research at Amgen in Thousand Oaks, California, and one of Crews’s early collaborators. The drug strategy, called targeted protein degradation, capitalizes on the cell’s natural system for clearing unwanted or damaged proteins. These protein degraders take many forms, but the type that is heading for clinical trials this year is one that Crews, based at Yale University in New Haven, Connecticut, has spent more than 20 years developing: proteolysis-targeting chimaeras, or PROTACs.
Large and unwieldy, PROTACs defy conventional wisdom on what a drug should be. But they also raise the possibility of tackling some of the most indomitable diseases around. Because they destroy rather than inhibit proteins, and can bind to them where other drugs can’t, protein degraders could conceivably be used to go after targets that drug developers have long considered ‘undruggable’: cancer-fuelling villains such as the protein MYC, or the tau protein that tangles up in Alzheimer’s disease.