Newly discovered molecules accelerate the removal of immune-modulating enzyme

Cells have a remarkable housekeeping system: proteins that are no longer needed, defective, or potentially harmful are labeled with a molecular "tag" and dismantled in the cellular recycling machinery. This process, known as the ubiquitin-proteasome system, is crucial for health and survival. Now, an international team of scientists led by CeMM, AITHYRA and the Max Planck Institute of Molecular Physiology in Dortmund has identified a new class of small molecules that harness this natural system to accelerate the removal of an immune-modulating enzyme called IDO1. The findings, published in Nature Chemistry (DOI: 10.1038/s41557-025-02021-5), introduce a new concept in drug discovery that could transform how we target difficult proteins in cancer and beyond.

Most drugs work as inhibitors: they block a protein's active site or prevent it from interacting with its partners. The protein itself, however, remains present in the cell. In contrast, the emerging field of Targeted Protein Degradation (TPD) takes a bolder approach – instead of just blocking, it eliminates disease-causing proteins altogether.

The molecular machinery required for this process is already present in the cell: proteins known as E3 ligases act as watchmen, recognizing proteins that should be destroyed. They attach a molecular label – called ubiquitin – that directs these proteins to the proteasome, the cell's recycling unit. TPD strategies usually involve designing small molecules that physically connect a target protein to an E3 ligase, forcing the ligase to tag it for destruction. This approach has already produced more than 30 drug candidates in clinical trials.

Inhibit and destroy

The newly discovered molecules – called iDegs – take this principle in a new direction. Instead of creating artificial connections, they boost an existing, natural pathway. The researchers found that iDegs bind to IDO1, an immune-modulating enzyme, in a way that makes it more susceptible to its native E3 ligase, KLHDC3. This means the molecules are not inventing a new route to degradation but rather pressing harder on a switch the cell already has in place. The result: IDO1 is both inhibited and destroyed more efficiently.

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. That is scientifically elegant because it works with the cell's own logic – and it is therapeutically powerful because it combines inhibition and elimination in one step."

Natalie Scholes, senior postdoctoral researcher at CeMM and co-first author of the study

Taking cancer's shield away

IDO1 (indoleamine-2,3-dioxygenase 1) metabolizes the amino acid tryptophan into kynurenine, a pathway that suppresses immune activity. Tumors and viruses alike use it as a shield against attacks of the immune system. So far, clinical trials with IDO1 inhibitors have disappointed as cancer drugs, likely also because IDO1 has non-enzymatic signaling roles that simple inhibition cannot neutralize. That's why the dual action of iDegs could be a game-changer: By both binding to the enzyme and accelerating its destruction, they take IDO1 off the table entirely. This not only reduces kynurenine production but also eliminates the enzyme's additional immunosuppressive roles.

The iDegs identified by the researchers are pseudo-natural products derived from myrtanol, a compound found in nature. Through structural biology and biochemical experiments, the team showed that iDegs displace IDO1's heme cofactor and shift the protein into a degradation-sensitive conformation. KLHDC3, which normally controls the baseline turnover of IDO1, then tags it more efficiently for destruction. For cancer immunotherapy, the implications are clear: removing IDO1 entirely could dismantle one of cancer's favorite defense strategies.

But the principle goes further, says Georg Winter, Director at the AITHYRA Institute for Biomedical AI, adjunct Principal Investigator at CeMM and co-senior author of the study: "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'."