Thursday, November 7, 2013

Applications: Screening for Small Molecule Inhibitors of BRD 4

BRD4 is a member of the bromodomain family of proteins which serve as epigenetic readers. Essentially there are 3 groups of important proteins that are involved in epigenetic regulation. Writers and erasers, enzymes which add and remove marks to DNA and associated proteins, and the epigenetic readers that determine how those marks are interpreted with resulting increased or decreased expression of genes.

Structure of the BRD4 protein.
Based on PyMOL rendering of PDB 2oss
by Emw 
The importance of epigenetic readers is indicated by their implication in a number of diseases and the search for inhibitors of these proteins is ongoing. BRD4 has been identified as a therapeutic target in advanced myeloid leukemia and other cancers as well as inflammatory diseases. In the recent article entitled: 'Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening' the authors describe an approach to mine new potential inhibitors based on knowledge of BRD4 structure. In order to validate these inhibitors they used an AlphaScreen based approach and chose the PHERAstar FS from BMG LABTECH to detect these biochemical assays.

The assay employed was previously described in a paper entitled: 'Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery.' It identifies the ability of bromodomains to bind to acetylated histone peptides via protein-protein interaction that can be detected using AlphaScreen technology.

We at BMG LABTECH are proud that our instruments could contribute in some way to this very interesting research!