'Major breakthrough' could expose new drug discovery

A team of researchers from the college of life sciences at the University of Dundee, Scotland has developed a novel approach for selectively targeting BET bromodomain proteins using small molecules.

If successful, scientists have suggested this new technique could be used unlock a huge new era of drug discovery for many diseases including cancer and inflammatory conditions.

“We have now developed a novel so-called ’bump-and-hole’ approach

Lead researcher Alessio Ciulli

BET bromodomain proteins are gathered in a set of eight sites within human cells, and have previously been identified as strong candidates for drug development.

Unfortunately, they are significantly limiting as the eight are so similar in nature, developing molecules that could effectively hone in on them individually has not been possible, the researchers said.

Alessio Ciulli, who led the research team, said that small-molecule compounds used to target the bromodomains had no selectivity or control, meaning that either all eight were targeted, or none were - a process which is not nearly refined enough to conduct the testing and drug development that are vital if this protein group is to be exploited for drug therapies.

“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,” Ciulli said.

“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.”

Ciulli said his research team’s targeting approach is similar to working on 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 [fixing]. That is the level of focus we are now able to reach with bromodomains as a result of our discovery,” Ciulli said.

“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,” he said.

According to researchers, the situation with bromodomain proteins is similar to breakthroughs made with protein kinases in the 1990s - a feat which is leading the majority of pharmaceutical companies to devote resources to its development.

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.”

The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and has been published in the journal Science.