Public Release: 

A kiss of death to drug the 'undruggable'

PROTAC cooperative recognition for selective protein degradation

University of Dundee


IMAGE: Image shows the E3 ligase protein VHL (in grey) in complex with the small molecule MZ1 (in raspberry) and 'kissing' the protein BRD4 (in yellow). Upon receiving this deadly `kiss',... view more

Credit: Xavier Lucas, Alessio Ciulli, University of Dundee

Scientists at the University of Dundee have reported a major breakthrough in targeting the causes of many diseases, using a `kiss of death' to destroy proteins which had previously been regarded as `undruggable'.

Much is known about proteins such as Ras and Myc which are known to be culpable in human cancer, and Huntingtin, which causes Huntingdon's disease, but as yet they have proved stubbornly resistant to efforts to find ways of tackling them with drugs.

Now researchers led by Professor Alessio Ciulli in the School of Life Sciences at Dundee have found a way of targeting similar proteins, using a small molecule approach in an unconventional way to target `bad' proteins by binding them to neutralising agents to start a process of degradation, and thereby removing them entirely.

"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," said Professor Ciulli.

"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 - these proteins can often fool regulators within the cell and be extremely difficult to pin down with inhibitors.


"Crucially, we have also 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."

Professor Ciulli and colleagues focused their attention on a bivalent chemical degrading molecule called `PROTAC' (Proteolysis-targeting chimeric molecules). They have been able to create the first X-ray crystal structure of a PROTAC bound to both the 'bad' protein and the 'neutralising' agent (an E3 ubiquitin ligase), and found that it can successfully be deployed as a `magnet' to draw the two target proteins together.

"This discovery provides the first ever insights into how PROTACs work and how we can target proteins for degradation in a highly selective manner," said Professor Ciulli.



The work done by the Dundee team focused on pairing one of the BET bromodomain proteins, BRD4, which is an attractive drug target for cancer, with a selective BRD4 `degrader' called MZ1. They found that MZ1 could pull the two proteins together by folding into itself. Once the two proteins are joined in their `kiss' the interactions between them lead to degradation of the target. They showed how similar proteins BRD2 and BRD3 do not kiss the neutralizing protein as well, and guided by this information they were able to design new degraders that spare those proteins completely from the degradation process. This is important because it elucidates how degrading molecules could be designed in future to minimize off-target effects in ways that may not be possible using conventional inhibitors.




