Bromodomain project

Epigenetic Targets to Fight Disease

Bromodomains (BRD) are small nuclear proteins that selectively bind to acetylated lysine residues of histone proteins. Once bound, these BRDs recruit protein complexes involved in chromatin structure regulation, and thus play a role in gene expression. The human proteome encodes 61 BRDs, which are present in 46 diverse nuclear and cytoplasmic proteins that are divided into eight major structural classes. The BRD and extra-terminal (BET) protein family, structural class II, includes BRD2, BRD3, BRD4 and BRDT. These proteins all play key roles in diverse cellular processes, such as inflammatory gene expression, mitosis and viral/host interactions, by linking acetylation marks to transcriptional regulation at promoters.

BET proteins have emerged as druggable targets for novel pharmacological therapy against neoplastic, viral, neurological, inflammatory and autoimmune disorders. Structure-activity relationships and co-crystal structure studies have identified design features that could enable a general structural platform for the rational design of BRD inhibitors.

In-house docking studies of the compounds from our proprietary library showed high docking scores for BRD2 and BRD4, suggesting strong interactions with the BET/BRD proteins. A discovery program is ongoing to identify and optimize small molecule inhibitors that disrupt BRD/histone interactions and as such have the potential to become the next generation therapeutics for human disease.

 

 

 

 

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