Each cell operates an unceasing molecular recycling process, labeling unwanted proteins with a chemical “destroy me” tag and channeling them into a cellular shredder. Researchers have aspired to take control of this mechanism, compelling it to eradicate disease-inducing proteins that conventional medications can’t target. A group of scientists has now discovered a method to achieve this, not by overpowering the cell’s machinery but by altering a cancer-related protein to resemble waste that the cell is already inclined to dispose of.
The research, published on January 7 in Nature Chemistry, outlines a new category of small molecules termed iDegs that expedite the breakdown of IDO1, an enzyme that tumors utilize to thwart immune attacks. Instead of merely inhibiting IDO1’s function, these molecules physically modify the protein, transforming it into a configuration that the cell’s inherent cleanup system finds irresistible.
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, the study presents a more nuanced strategy for targeted protein degradation. Rather than artificially forcing proteins together like molecular duct tape, iDegs enhance decisions that cells already intuitively make.
Shifting the Equilibrium Toward Natural Degradation
The key lies in how iDegs interact with IDO1. The molecules embed into a deep cavity within the enzyme and displace a crucial component known as a heme cofactor. This displacement results in a significant structural alteration, effectively unfolding a portion typically concealed. The revealed tail serves as a vivid flag for KLHDC3, a cellular sentinel that marks proteins for destruction.
High-resolution structural imaging elucidated the mechanism in detail. Upon iDeg binding, it compels IDO1 into a configuration that KLHDC3 readily identifies as unstable. This leads to accelerated tagging and removal via the ubiquitin-proteasome system, the cell’s primary protein recycling pathway.
“iDegs unveil an entirely novel principle for drug discovery. They demonstrate that small molecules can shift the balance in favor of a protein’s natural degradation, rather than artificial rerouting,” Natalie Scholes, senior postdoctoral researcher at CeMM, clarifies.
This dual impact addresses a constraint of conventional inhibitors. Traditional medications may obstruct an enzyme’s active site, yet they leave the protein within the cell. IDO1, which metabolizes the amino acid tryptophan into kynurenine, appears to possess immune-suppressive roles beyond its enzymatic function. Simply disabling the active site maintains those other signals. The iDegs entirely eliminate the protein.
For cancer immunotherapy, this distinction is crucial. IDO1 aids tumors in evading immune detection by suppressing T-cell activity. Clinical trials of IDO1 inhibitors have generally fallen short, potentially because inhibiting the enzyme alone wasn’t sufficient. Complete elimination could deprive tumors of one of their most potent defensive strategies.
Enhancing Existing Circuits
The researchers characterize iDegs as pseudo-natural products, derived from myrtanol, a naturally occurring compound. Their studies revealed that many proteins naturally oscillate between stable and unstable states. If drugs can selectively promote targets toward their unstable versions, scientists might be able to address proteins previously deemed unmanageable.
The discovery reframes drug development as less about brute force and more about synergy with cellular machinery. Most current protein degraders function by forging artificial connections between a target protein and an E3 ligase, the overseer that determines what is marked for destruction. While effective, these designs create associations that the cell doesn’t typically utilize.
The iDegs adopt an alternative approach. They don’t drag anything to disposal. They simply indicate that the waste needs removal, aligning with the cell’s pre-existing quality-control regulations rather than bypassing them.
Beyond IDO1, the research implies a broader principle. If other proteins harbor similar concealed switches that trigger natural degradation pathways, this enhanced method could apply across a variety of diseases. The next generation of therapies may not only impede disease advancement but physically eliminate its molecular origins, providing nature’s recycling system with a timely boost.
[Link to study: Nature Chemistry: 10.1038/s41557-025-02021-5]