Development of a Selective Bromodomain Inhibitor Involved in the SWI/SNF Chromatin Remodeling Complex

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The DNA contains the instructions for making all the proteins of a species. To fit inside the nucleus of a cell, the DNA wraps itself around proteins called histones, leading to the formation of chromatin. Euchromatin is lightly packed and available for gene expression whereas heterochromatin is dense and not accessible for transcription. The way chromatin is packed is regulated by epigenetic enzymes that install and remove small fragments called epigenetic marks on DNA and histones and by chromatin remodeling complexes that change its shape. Epigenetic readers interact with these marks to initiate gene transcription. Bromodomain containing proteins (BCPs) are epigenetic readers that interact with acetylated lysine side chains on histones and that recruit transcription factors to launch the transcription of genes. BCPs were found to be overexpressed in many cancers, leading to elevated expression of cancer-associated genes. Interaction of small molecules with BCPs disrupts their interaction with histones thus preventing the expression of oncogenes. However, most BCPs inhibitors share a common structure and are thus expected to suffer from the same liabilities. Therefore, new BCPs inhibitors are urgently needed to provide novel and alternative strategies to combat cancer. The goal of this project is to develop an inhibitor of BPCs that are part of the switch/sucrose nonfermenting SWI/SNF chromatin remodeling complex, an underexplored medicinal chemistry target that will be used as a chemical probe to investigate the role of SWI/SNF in gene expression. This project involves a multidisciplinary team of scientists at UQAM in Montreal and Zenith Epigenetics Ltd. in Calgary in the complementary fields of synthetic and medicinal chemistry, biology, biochemistry, biophysics and pharmacology. This project will contribute to the training of highly qualified personnel that will be able to take on challenging jobs in Canadian biopharmaceutical companies and to the advancement of knowledge in the field of epigenetics that will be used by the industrial partner to develop new programs that could result in job creation. Ultimately, this project could lead to new strategies to treat cancer, thus contributing to the health of Canadians.