A new study led by researchers from the CeMM Research Center for Molecular Medicine and the AITHYRA Institute for Artificial Intelligence in Biomedicine, both institutes of the Austrian Academy of Sciences in Vienna, and the IRB Barcelona shows that many kinase inhibitors – central active ingredients in cancer medicine – not only block the activity of disease-causing enzymes, but also degrade them. The results were published in “Nature” on 26 November 2025 (DOI: 10.1038/s41586-025-09763-9) and open up new avenues for targeted protein degradation therapy.

Kinase inhibitors, of which over 80 are FDA-approved and twice as many are in clinical trials, are designed to stop cancer cells by blocking uncontrollably active kinase switches. The study tested 1,570 inhibitors on 98 kinases in cell cultures and found that 232 drugs reduced the concentration of at least one kinase, and a total of 66 kinases were affected.

The degradation takes place in part via the well-known “chaperone deprivation” mechanism: If an inhibitor binds to the kinase, the protective protein HSP90 can no longer be effective, and the cell breaks it down. More often, however, inhibitors shift the kinase into unstable states – through changes in activity, cell displacement, or aggregation – which the cellular quality control system recognizes and disposes. Three examples illustrate this: LYN is degraded by a stability switch, BLK after a diaphragm shift, RIPK2 by aggregate formation.

“We were surprised at how widespread this effect is,” says first author Natalie Scholes from CeMM. “Inhibitors actively destabilize proteins – this expands their therapeutic potential enormously.” Study leader Georg Winter (AITHYRA/CeMM) adds: This mechanism could promote the development of new “degrader” drugs that specifically eliminate disease-causing proteins and explain unexpected therapeutic successes.

Original Paper:

DOI: 10.1038/s41586-025-09763-9

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