Every cell runs a tireless molecular recycling operation, tagging unwanted proteins with a chemical “destroy me” label and feeding them into a cellular shredder.
Scientists have long wanted to commandeer this system, forcing it to eliminate disease-causing proteins that regular drugs can’t touch. A team of researchers has now found a way to do exactly that, not by overpowering the cell’s machinery but by making a cancer-critical protein look like garbage the cell already wants to throw out.
The study, published January 7 in Nature Chemistry, describes a new class of small molecules called iDegs that accelerate the destruction of IDO1, an enzyme tumors use to suppress immune attacks. Rather than simply blocking IDO1’s activity, these molecules physically reshape the protein, pushing it into a form the cell’s natural cleanup system finds irresistible.
The work, led by scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, AITHYRA, and the Max Planck Institute of Molecular Physiology, introduces a subtler approach to targeted protein degradation. Instead of artificially forcing proteins together like molecular duct tape, iDegs amplify decisions cells already know how to make.
Tipping the Balance Toward Natural Destruction
The trick lies in how iDegs interact with IDO1. The molecules nestle into a deep pocket within the enzyme and displace a core component called a heme cofactor. This displacement causes a dramatic structural shift, essentially unfolding a section normally tucked away. The exposed tail acts as a bright flag for KLHDC3, a cellular watchman that tags proteins for destruction.
High-resolution structural imaging revealed the process in detail. When an iDeg binds, it forces IDO1 into a shape that KLHDC3 already recognizes as unstable. The result is faster tagging and elimination through the ubiquitin-proteasome system, the cell’s main protein recycling pathway.
“iDegs highlight an entirely new principle for drug discovery. They show that small molecules can tip the balance in favor of a protein’s natural destruction, instead of artificially rerouting it,” Natalie Scholes, senior postdoctoral researcher at CeMM, explains.
This dual effect addresses a limitation of classic inhibitors. Traditional drugs might block an enzyme’s active site, but they leave the protein sitting in the cell. IDO1, which breaks down the amino acid tryptophan into kynurenine, appears to have immune-suppressive functions beyond its enzymatic role. Simply disabling the active site leaves those other signals intact. The iDegs remove the protein altogether.
For cancer immunotherapy, the distinction matters. IDO1 helps tumors evade immune surveillance by dampening T-cell responses. Clinical trials of IDO1 inhibitors have largely failed, possibly because blocking the enzyme wasn’t enough. Eliminating it entirely could strip tumors of one of their most effective defensive mechanisms.
Amplifying Circuits Already Present
The researchers describe iDegs as pseudo-natural products, derived from myrtanol, a compound found in nature. Their experiments showed that many proteins naturally cycle between stable and unstable states. If drugs can selectively push targets toward their unstable forms, scientists might be able to tackle proteins once considered impossible to drug.
The finding reframes drug discovery as less about brute force and more about collaboration with cellular machinery. Most current protein degraders work by creating artificial bridges between a target protein and an E3 ligase, the gatekeeper that decides what gets tagged for destruction. While effective, those designs create connections the cell doesn’t normally use.
The iDegs take a different route. They don’t drag anything to the curb. They just make it obvious the trash needs to go, working within the cell’s existing quality-control rules rather than overriding them.
Beyond IDO1, the study suggests a broader principle. If other proteins have similar hidden switches that trigger natural degradation circuits, this supercharging approach could extend to a range of diseases. The next generation of medicines might not just block disease progression but physically remove its molecular causes, giving nature’s recycling system a well-timed nudge.
Nature Chemistry: 10.1038/s41557-025-02021-5
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