Institute of Cancer Research Scientists Create Next-Generation Aurora A PROTAC Tool for Targeted Protein Degradation Research

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(IN BRIEF) Researchers at The Institute of Cancer Research, London have created a next-generation PROTAC degrader that successfully eliminates the cancer-related protein Aurora A while overcoming the hook effect that has limited earlier degraders. The new molecule, CCT400028, demonstrates improved stability, selectivity, and sustained activity, enabling reliable degradation across a broader concentration range. Tested in paediatric cancer cell models, the degrader provides a powerful research tool for studying Aurora A biology and may inform the future design of targeted protein degradation drugs. The work, supported by Cancer Research UK and carried out in collaboration with the University of Kiel, represents an important methodological advance that could influence the development of more effective PROTAC tools and therapies.

(PRESS RELEASE) LONDON, 27-Feb-2026 — /EuropaWire/ — The Institute of Cancer Research, London (ICR) has developed a new generation of targeted protein degrader molecules that overcome a major obstacle in the design of PROTACs, enabling more effective elimination of the cancer-related protein Aurora A. The advance represents an important step toward improving research tools and potentially guiding the future development of targeted protein degradation therapies.

The research team demonstrated the successful design of a second-generation PROTAC degrader capable of selectively eliminating Aurora A, a protein strongly linked to cancer cell growth and poor clinical outcomes. Aurora A plays a central role in cell division, contributing to processes such as mitotic spindle formation, chromosome alignment, and centrosome maturation. While tightly regulated in healthy cells, Aurora A is frequently dysregulated in many cancers. Traditional kinase inhibitors have struggled to fully suppress Aurora A activity because the protein also functions as a scaffold that supports multiple cellular interactions. Targeted degradation offers a more comprehensive strategy by removing the entire protein rather than blocking a single function.

The study addressed a long-standing challenge in PROTAC development known as the hook effect, a phenomenon in which degradation efficiency declines at higher drug concentrations. This occurs when PROTAC molecules bind separately to either the target protein or the E3 ubiquitin ligase, preventing formation of the three-component complex required for protein destruction. The hook effect has limited the performance and usefulness of many PROTAC molecules.

Researchers overcame this limitation through rational molecular engineering. Using the investigational Aurora A inhibitor alisertib as a structural foundation, the team designed a second-generation degrader called CCT400028. By reducing the binding strength between the PROTAC molecule and the E3 ligase, the scientists improved the formation of productive ternary complexes and effectively eliminated the hook effect. Laboratory experiments demonstrated that the optimized molecule maintained strong activity across a wider range of concentrations without loss of degradation performance.

The redesigned molecule also showed significantly improved stability. The new degrader achieved a half-life exceeding 120 hours in cell culture experiments, compared with approximately 25 hours for earlier versions, allowing sustained Aurora A depletion over extended experimental periods. Tests in paediatric cancer cell lines, including leukaemia, neuroblastoma, and glioma models, confirmed consistent and durable degradation of the target protein.

Selectivity was another major improvement. The CCT400028 degrader demonstrated strong specificity for Aurora A without binding to other kinases or degrading unrelated proteins, reducing the risk of unintended off-target effects seen in earlier approaches. The researchers also created a matched inactive control molecule to support reliable experimental interpretation, enabling scientists to distinguish between specific degradation effects and unrelated cellular responses.

CCT400028 has been recognised as a high-quality chemical probe and is recommended by the Chemical Probes Portal as a leading Aurora A degrader for laboratory use. The molecule provides researchers with a precise tool for studying Aurora A biology and complements genetic techniques by allowing controlled, time-dependent protein depletion.

The project was led by scientists at The Institute of Cancer Research, London, with support from Cancer Research UK through the Children’s Brain Tumour Centre of Excellence and collaboration with researchers at the University of Kiel in Germany. The findings were published in the Journal of Medicinal Chemistry.

Beyond Aurora A, the work offers broader insights into the design of targeted protein degraders. The researchers believe that strategies developed to eliminate the hook effect may be applicable to PROTAC programs aimed at other disease-related proteins, helping to advance the development of future chemical probes and therapeutic candidates.

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SOURCE: The Institute of Cancer Research