Library of Small Molecule Modulators & Inhibitors of Bromodomains
Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signaling and disease biology. Enzymes that write histone acetyltransferases (HATs) and erase (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few selective and potent modulators of the „reading process have been described. Bromodomains (BRDs) are evolutionary conserved protein interaction modules that specifically recognize ε-N-lysine (KAc) acetylation motifs, a key event in thereading process of epigenetic marks.
Bromodomains are named after the Drosophila gene brahma where they were first identified. These domains have been observed as part of numerous larger protein architectures, many of which are involved in regulating gene transcription, including HATs, ATP-dependent chromatin-remodeling complexes, methyltransferases, and transcriptional coactivators. There have been 61 bromodomains identified in the human proteome, which are found within 46 separate proteins, and that can be phylogenetically divided into eight distinct families [Cell 2012; 149: 214].
The precise cellular role of most bromodomain containing proteins (BCPs) is still unknown. However, those BCPs that have been studied in detail have been linked to certain diseases, and this work has been extensively reviewed [J Med Chem. 2012; 55: 9393]. As bromodomains are invariably components of large multidomain proteins, removal of the whole BCP does not provide information on the specific function of the bromodomain itself. Consequently, an important strategy in the study of bromodomain function is the development of small molecule effectors that selectively prevent the interaction of a given bromodomain with KAc, without affecting other functions of the BCP.
The large number of diseases that have been linked to BRD-containing proteins and the success of particular HDAC inhibitors indicate that BRD inhibitors will find a large number of applications in drug discovery and academic research. The relatively weak interaction of BRDs with their substrates, the diversity and physicochemical properties of the acetyl lysine binding site, and the large number of available crystal structures will facilitate the rational design of such inhibitors.
ChemDiv proposes the new library of BRDs inhibitors/modulators. This library represents a selection of drug-like compounds aimed at modulating protein-protein interaction of BCPs with different proteins involved in significant physiological processes. Library has been assembled using in house structural biology insight, molecular stimulation-modeling, virtual screening of ChemDiv‟s novel chemistries and medicinal chemistry filtering/ranking of the resulting hits. Evaluation of the rich body of structural information on bromodomains enabled detailed family-wide structural analysis of the human BRD family and its “druggability”. ChemDiv combined a number of in silico screening approaches and spatial information of putative acetyl-lysine mimetics to identify chemical starting points for the development of BRDs inhibitor library.