Product Development for Bromodomain Networks: Abstract: 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 readers 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 Phase II application we?ll concentrate on 3 major works: 1) to complete the screening of Bromodomains against the FDA approved drugs and NIH?s clinical trial agent collections for identifying new probes and building the chemical-epigenetic data base; 2) to expand the HTS efforts to include 4 to 7 new BRDs as potential drug targets. These bromodomains will be good potential drug targets, but have no probes or lack of good probes based on public domain information; and 3) to develop potent and selective probes by SAR studies and evaluate their activities in cell based assays. The lead compounds with unique scaffolds will be further tested with DMPK-Tox assays as potential therapeutic agents.
Product Development for Bromodomain Networks: Narrative: 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 Phase I research, and extend the probe discoveries into new bromodomains that have no probes available. We will also continue to develop all possible reagents and assays to provide them as products and services for our customers.
