Epigenetic regulation of gene expression is a highly dynamic and reversible process essential to normal cellular function. However, it also contributes to human diseases, such as cancer and inflammation. Protein families that participate in epigenetic regulation include writers, which covalently modify chromatin; readers, which recognize chromatin modifications; and erasers, which remove modifications. A large volume of research in the field over the past decade has shown that many epigenetic proteins are potential druggable targets. Bromodomains, which belong to the reader's category, recognize acetylated lysine residues on histones and other proteins. Several potent, selective and cellularly active bromodomain compounds have recently been identified, increasing appreciation of the functional importance and therapeutic potential of this family. However, studies are limited and focus only on a few bromodomain subfamilies, such as the bromodomain and extraterminal (BET) proteins. There are a number of reasons that the studies have not expanded into more reader proteins; the key limitations are in both the availabilities of products and the body of knowledge for these non-BET subfamily targets. As part of the proposed project, we will systematically develop 1) complete, high-quality bromodomain proteins, 2) substrate knowledge for each target, 3) multiple assay formats for each target, 4) probe(s) for each target, 5) easy-to-use assay kits, 6) assay services for newly produced reader domains, and importantly, 7) the first drug-bromodomain interaction database, which we will build by testing each bromodomain against a large number of FDA-approved drugs and agents in clinical trials, to provide information on how these commonly used drugs and chemicals affect epigenetic activities relevant to human health.
Epigenetic regulation of gene expression is a highly dynamic and reversible process essential to normal cellular function. However, it also contributes to human diseases, such as cancer and inflammation. Over the past decade, many studies have shown epigenetic proteins to be potential druggable targets. One epigenetic family of interest is the readers, which recognize specific chromatin modifications. Bromodomains are epigenetic readers that recognize acetylated lysine residues on histones and other proteins. Several potent, selective and cellularly active bromodomain compounds have recently been identified, increasing interest in the functional importance and therapeutic potential of this family. The limited studies available, however, focus on only a few bromodomain subfamilies, particularly the bromodomain and extraterminal domain (BET) proteins. Reaction Biology Corporation ('RBC') is poised to systematically produce all protein targets, assay reagents and assay formats for screening probes to advance research and drug discovery efforts in this important but fledgling field. RBC is a successful SBIR applicant with a proven track record of protein and assay commercialization in many key drug target families, including human kinases and methyltransferases. In the proposed project, we will build on the successes of our grants to date, moving to the bromodomain family. We will develop all possible reagents and identify epigenetic chemical probes by assaying proven, public small molecule collections. Probes that are identified will have great potential value as both research tools and therapeutic agents.
