A group of scientists at The Institute of Cancer Research (ICR), London, in joint efforts with the company Malvern Instruments, design a molecule that blocks the action of a protein called TLE1, which is part of different signalling networks linked to cancer.
For the study, the researchers visualized the TLE1 protein in 3D, to find a specific shape for the desired molecule, in order it could bind tightly to the protein, stopping it from doing its function. Once they find it, they build up the molecule from smaller units, using a process called stapled peptide synthesis.
The authors of the research, published in Chemistry: A European Journal, think their findings could be the starting point for discovering a new an anti-cancer drug in the future.
Normally, TLE1 forms part of a number of signalling pathways that allow healthy cells to communicate within each other, including two called the Notch and Wnt pathways. This communication allows adjacent cells knowing if they should divide and, if so, into which kind of cell they have to differentiate. However, in cancer, these pathways may act abnormally, causing uncontrolled growth.
Therefore, the researchers believe that blocking TLE1 action may help disrupting this process, slowing or even stopping growth of cancerous cells. So, they design the new molecule based on a short protein chain, which is present in many of the proteins that TLE1 binds to in cells. Then, they introduced an extra four carbon atoms to tie two parts of the molecule together, which acted as a ‘staple’, locking the molecule in an orientation that lined it up with TLE1.
“TLE1 has been implicated in a number of different cancers, making it a promising possible target for future treatments,” said study leader Dr. Swen Hoelder, ICR Team Leader in Medicinal Chemistry. “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.”