Cancer could be wiped out after scientists discover how to destroy key proteins thought to be ‘untouchable’
Researchers can now target cancer-causing proteins by using molecules to bind them to a neutralising agent that kills them
Cancer could soon be eradicated after a breakthrough discovery that kills previously ‘undruggable’ proteins that cause the illness.
British scientists have developed a ‘kiss of death’ for the proteins, which they know also cause conditions such as Huntingdon’s disease, but have been resistant to drugs.
The team, from the University of Dundee in Scotland, can now target these proteins by using molecules to bind them to a neutralising agent.
Professor AlessioCiulli at Dundee’s School of Life Sciences said: “Crucially, we have found that it is not enough for this neutralising protein to sit close to the bad protein.
“It has to make direct contact with it, to ‘kiss’ it and not just a little peck, but a real ‘Gone with the Wind’ embrace.
“We call this a ‘kiss of death’, as it is the key to ensure the degradation of the bad protein.
“We know of many proteins which are active in causing diseases, but which we have been unable to block from going rogue or to stop them when they do.
“The major problem is that we have been unable to find the small molecules which can successfully bind to these proteins and at the same time hamper their function.
“It is a highly complex area as these proteins can often fool regulators within the cell and be extremely difficult to pin down with inhibitors.
“Research in our lab in the past few years has contributed towards establishing a different approach, one that has been theorised for many years but which is only now fully realised by this latest work.
“Instead of using the small molecule to try and disable the bad protein, we have developed a way of modifying it so that it can be used to attract the neutralising proteins, which then bind to their bad neighbour and act against it, starting a cascade process of degradation.”
Much is known about proteins, including Ras and Myc which are known to be culpable in cancer, and Huntingtin, which causes Huntingdon’s disease, but as yet they have proved stubbornly resistant to efforts to tackle them with drugs.
Now scientists hope these ‘undruggable’ proteins can be removed completely.
For the paper, published in the journal Nature Chemical Biology, they looked at a bivalent chemical degrading molecule called PROTAC (Proteolysis-targeting chimeric molecules).
They created the first X-ray crystal structure of a PROTAC bound to both the bad protein and the neutralising agent and found that it can successfully be used as a magnet to draw the two target proteins together.
Prof Ciulli added: “This discovery provides the first ever insights into how PROTACs work and how we can target proteins for degradation in a highly selective manner.
“This presents a paradigm shift in how we can ensure selective chemical intervention against proteins which we know are factors in causing disease but which until now have been impossible to successfully target.
“It points towards the possibility of drugging the undruggable.
“We now understand better how to turn inhibitors into degraders.
“The road to turning degraders into drugs will be long and winding but it is exciting to see signs of serious commitment from the pharmaceutical industry, which adds to the optimism.” – Story courtesy of The Sun