University of Dundee

Ciulli Lab's bump-and-hole approach leads to protein breakthrough

22 Oct 2014

A major breakthrough by scientists at the University of Dundee in the study of a set of human proteins has the potential to unlock a huge new area of drug discovery for many diseases including cancer and inflammatory conditions.
The research team led by Dr Alessio Ciulli in the College of Life Sciences at Dundee have developed a new method of selectively targeting the proteins known as BET bromodomains using small molecules.
The results of the research, which has been funded by the Biotechnology and Biological Sciences Research Council, are published in the prestigious journal Science.
The BET bromodomains are gathered in a set of eight sites in our cells. They had previously been identified as being strong targets for drug development but there was a significant limitation in that, because the eight are all so similar in nature, it has been not possible to develop molecules that could hone in on them individually.
“The problem there has been is that the small-molecule compounds being used to target the bromodomains had no selectivity or control – we could basically target all of the eight or none, which is not nearly refined enough to do the sort of testing and drug development that are vital if we are to exploit this area for drug therapies,” said Dr Ciulli.
“We have now developed a novel so-called `bump-and-hole’ approach where it is possible to target at will one or more of the BET bromodomain sites without touching the others. This allows us to ask important scientific questions and to carry out significantly more refined experiments which will produce much valuable data to further elucidate how these proteins work and how to more effectively target them therapeutically.
“This is a bit like having a car engine - if you have a problem and want to figure out where exactly the fault is, you don’t want to replace the entire engine, you want to deal with the specific bit that needs fixed. That is the level of focus we are now able to reach with bromodomains as a result of our discovery.
“This is significant because BET proteins are a growing area of interest to the scientific community in chemical biology and have demonstrated huge potential as targets in drug discovery.
“This field has boomed in the last four years and almost every pharmaceutical company is devoting significant resources to it, so this breakthrough we have made could have huge impact. The situation with bromodomain proteins now is similar to what we saw with protein kinases in the early 1990s, where a similar breakthrough has helped lead to that becoming a multi-billion pound area of research and drug discovery for the pharmaceutical sector.”
Dr Ciulli said the approach he and his team developed was similar in concept to that used on protein kinases.
“The specific concept of `bump and hole’ has been used before in protein kinases but we are the first to show it can be done on binding sites that involve a protein-protein interaction. These interactions are much more difficult to target than enzyme active sites such as those that had been targeted in kinases.”
“Because of these challenges, many thought that the approach would be too risky and would not work on bromodomains. We nevertheless were able to convince our funding bodies, principally the Biotechnology and Biological Sciences Research Council (BBSRC) that the idea had appropriate risk/gain balance, groundbreaking potential and was worth supporting.”
Professor Dario Alessi, Director of the Medical Research Council Protein Phosphorylation & Ubiquitylation Unit at the University of Dundee, said, “Kinases have become one of the most important class of drug targets – almost 30 kinase drugs have been approved in recent years and are transforming the treatment of several types of cancer and inflammatory conditions.
“Important research has provided persuasive evidence that BET proteins could be similarly attractive drug targets as kinases. Dr Ciulli’s work represents a breakthrough that I expect will be rapidly exploited and accelerate development of a new class of drugs that target BET proteins.”