There is increasing interest in the role of epigenetic changes – functional modifications of the genome that do not involve changes to the genetic code itself – in health and disease. Histones assist in the efficient and correct packaging of DNA (chromatin) and are key targets for epigenetic modification by, for example, binding by bromodomains of which there are >60 known examples in >40 human proteins. Misregulation of the so-called Bromo and Extra-Terminal (BET) proteins, a subfamily of four proteins (Brd2, Brd3, Brd4 and Brdt) that each contain two bromodomain units, have been implicated in diseases such as cancers and inflammation.
Several inhibitors of the BET bromodomains-histone interaction are showing promise in early clinical trials and creating great interest in this area of drug discovery. However, many of the current inhibitors are pan-selective across the BET bromodomain subfamily and there remains an ongoing need for better tools to selectively explore the role of single BET bromodomains or proteins. Researchers at Dundee have developed a robust method for selectively interrogating BET domains individually by introducing a single-point mutation that does not significantly affect the native domain structure, binding affinity and protein function. The strategy permits the design of complementary inhibitors that can selectively bind the mutated BET bromodomain without inhibiting the wild type. The methodology was successfully applied to a single BET bromodomain protein (Brd4) to show that the binding of the first bromodomain of Brd4 is sufficient to displace Brd4 from chromatin. Together this new strategy offers a powerful route to interrogate the role of single bromodomains in health and disease and for drug discovery programmes. Several novel structures with optimized BET domain selectivity and mutants with improved characteristics have been developed that will be of value for future drug development.
This reseach was funded by a grant from BBSRC.