Study Identifies New Class of Small Molecules that Accelerates Protein Degradation

Cells maintain their health through a precise cleanup process that identifies and dismantles proteins no longer needed or potentially harmful. This system, known as the ubiquitin-proteasome pathway, labels unwanted proteins with molecular tags before recycling them. An international team led by CeMM, AITHYRA, and the Max Planck Institute of Molecular Physiology has discovered a new class of small molecules that use this natural process to accelerate the removal of an immune-regulating enzyme called IDO1. The findings, published in Nature Chemistry, introduce a new direction for drug discovery focused on protein degradation.

Most drugs inhibit proteins by blocking their activity or interactions, yet the proteins remain inside cells. The field of Targeted Protein Degradation (TPD) instead eliminates disease-causing proteins entirely. It relies on the cell’s own molecular machinery: E3 ligases that tag specific proteins for breakdown. These ligases attach ubiquitin molecules to proteins that are destined for the proteasome, where they are dismantled. TPD strategies commonly design small molecules that connect a target protein to an E3 ligase, triggering its destruction. More than 30 compounds using this idea are already in clinical testing.

The newly found molecules, called iDegs, refine this concept. Instead of artificially linking proteins to E3 ligases, iDegs strengthen an existing pathway. The research team showed that iDegs bind to IDO1 in a way that makes it easier for the enzyme’s natural ligase, KLHDC3, to tag it for removal. This means IDO1 is both inhibited and degraded more efficiently. “iDegs highlight an entirely new principle for drug discovery,” said Natalie Scholes, co-first author of the study. “They show that small molecules can tip the balance in favor of a protein’s natural destruction, instead of artificially rerouting it.”

IDO1 normally converts tryptophan into kynurenine, dampening immune responses. Tumors and viruses exploit this pathway to escape immune detection. Earlier drugs that only blocked IDO1 were unsuccessful, likely because they did not address the enzyme’s additional roles. iDegs, derived from the naturally occurring compound myrtanol, push IDO1 into a state that promotes its destruction by KLHDC3. Co-senior author Georg Winter explained that this strategy could be extended to other proteins. “With iDegs, we open the door to a new generation of degraders. That idea could be applied far beyond IDO1—many proteins that cycle between stable and unstable states might also have natural degradation circuits that are underappreciated. If we can learn to amplify them, we may be able to tackle targets that have long been considered undruggable.”