Scientists have used structure-based drug design to identify a chemical probe that fits proteins implicated in some cancers like a 3D jigsaw puzzle.
A team from The Institute of Cancer Research, London, and the University of Oxford’s Structural Genomic Consortium searched for molecules with a specific 3D shape to inhibit two proteins called BAZ2A and BAZ2B – members of a family of proteins called bromodomains that bind to histones, proteins around which the DNA is wrapped in the cell nucleus, and part of the cellular machinery that controls gene expression.
They found a new molecule with a shape that allowed it to latch on precisely to the bromodomain BAZ2, like two pieces of a jigsaw coming together.
The new molecule blocks the activity of BAZ2 – which plays an important role in prostate cancer relapse and in a type of childhood leukaemia in cancer cells. The new chemical probe was more than 100 times more potent than the molecule they had started with.
The findings underscore that 3D drug design can discover molecules that can block proteins which were previously difficult to target.
The study was published in the Journal of Medicinal Chemistry, and was funded by Cancer Research UK, the Wellcome Trust and the NIHR Biomedical Research Centre at The Royal Marsden Hospital NHS Foundation Trust and the ICR.
Bromodomains are a type of protein involved in a process called gene transcription, which controls how genes are switched on and off in our cells. Some bromodomains have been found to influence genes important for the development of cancer and drugs that can block their activity could be a new way to treat the disease.
Current bromodomain inhibitors bond to the molecule by mimicking the chemical properties of a compound called acetylated lysine. The area that bonds with acetylated lysine in these bromodomains is in the shape of a deep pocket, so other probes with a similar structure are also likely to work.
However, the acetylated lysine pocket on BAZ2 is very shallow compared with other bromodomains, which means the molecular shape of inhibitors must be much more closely aligned in order to fit. The usual types of inhibitor don’t work on it.
Scientists at the ICR and Oxford used structure-based design to find molecules that act as chemical probes to inhibit BAZ2 activity in cancer cells.
From an initial screening process they identified a probe that could weakly inhibit BAZ2 activity, and mapped out its crystal structure to find more potent inhibitors.
Through two rounds of structural design, they were able to find chemical probes that could closely bind with BAZ2 and were more than 100 times more potent as inhibitors than their starting point.
The probe had two flat molecular regions which came together to form a 3D structure that bonded with the shallow acetylated lysine pocket on BAZ2.
They tested their chemical probe and found that it successfully inhibited BAZ2 in cancer cells.
The findings show that structure-based drug design can develop powerful bromodomain inhibitors. The BAZ2 inhibitor is freely available online, enabling researchers to further investigate the role of BAZ2A and BAZ2B in cancer and normal cells.
Dr Swen Hoelder, Leader of the Medicinal Chemistry team at the ICR, said: “Structure-based drug design is like doing a 3D jigsaw puzzle, but with only half the pieces – you have a protein you want to inhibit and you need to find compounds with just the right shape to fit. Bromodomains are an important class of cancer targets but potent and specific inhibitors are needed to probe the role of individual bromodomains in cancer. Our collaboration with Oxford’s Structural Genomics Consortium has led to such a probe for BAZ2 bromodomains which are implicated in prostate cancer and leukaemias.”