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Scientists build molecule to disrupt cancer protein

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Researchers have designed and built a molecule that blocks the action of a protein linked to tumour development.

The protein, called TLE1, is part of a number of signalling networks linked to cancer, which makes it an attractive target for drugs to treat.

The team used 3D visualisations of TLE1 to determine what shape the molecule needed to be in order to bind tightly to it, and stop the protein from doing its job.

They then used a process called stapled peptide synthesis to build the molecule up from smaller units.

The study, from scientists at The Institute of Cancer Research, London, and the company Malvern Panalytical, found that the molecule bound well to TLE1 – suggesting it could be a starting point for future drug discovery research.

The research was funded by Cancer Research UK and Wellcome, and published in Chemistry: A European Journal.

Communication problems

In healthy tissue, TLE1 plays a role in helping cells to develop normally. It forms part of a number of signalling pathways that allow cells to communicate with one another, including two called the Notch and Wnt pathways.

Through this communication, neighbouring cells can determine whether they should divide and, if so, what type of cell they should grow into.

However, in cancer these pathways can become deregulated causing uncontrolled growth. As a result, blocking TLE1 from working could help to disrupt this process and slow or stop the growth of cancerous cells.

In a bind

The molecule was based on a short protein chain found in many of the proteins that TLE1 binds to in cells.

The team introduced an extra four carbon atoms to tie two parts of the molecule together. These acted as a ‘staple’, locking the molecule in an orientation that lined it up with TLE1 – hence the ‘stapled peptide’ name of the technique.

Having demonstrated that the technique is a viable option for blocking targets like TLE1, the team now hopes that future research will be able to further improve the chain’s affinity for the protein.

Study leader Dr Swen Hoelder, Team Leader in Medicinal Chemistry at the ICR, said: “TLE1 has been implicated in a number of different cancers, making it a promising possible target for future treatments.

“Our work showed that it is possible to design a short peptide chain to bind TLE1, which we hope will serve as the basis for the development of future TLE1 inhibitors. It also demonstrates the challenges in using this technique for designing and synthesising future cancer drugs.”


Swen Hoelder
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