‘Kiss of death’ for cancer cause
Scots scientists reveal breakthough in killing off ‘undruggable’ proteins
DISEASES like cancer could be eradicated after a breakthrough discovery means previously “undruggable” proteins that cause the illness can be destroyed.
Scottish 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 can now target these proteins by using molecules to bind them to a neutralising agent.
Professor Alessio Ciulli 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.
“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 which are known to be culpable in human cancer, but as yet they have proved stubbornly resistant to efforts to find ways of tackling them with drugs. Now they hope these “undruggable” proteins can be removed completely.
For the paper, published in the journal Nature Chemical Biology, they looked at a 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 deployed as a “magnet” to draw the two target proteins together.
Mr 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 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.”