Synthesis of Small-Molecule Inhibitors Targeting Bromodomain Containing Proteins

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The genetic information of an organism is contained within its DNA sequence. In order to fit inside the nucleus of a cell, DNA wraps itself around an octamer of proteins called histones, resulting in formation of chromatin. Epigenetic transformations, which consist in the installation of marks on DNA and histone tails, affect the level of compaction of chromatin, resulting in gene activation or silencing. Lysine acetylation is an epigenetic transformation that leads to the removal of the positive charge on the amino group of the lysine side chain thus preventing the formation of electrostatic interactions with the phosphate groups of DNA and resulting in gene transcription. Bromodomains are reader epigenetic proteins that bind to acetylated lysines to recruit transcription factors and promote gene transcription. A few bromodomain inhibitors have been reported and used as chemical probes to better understand the role of these proteins in chromatin remodeling and gene expression. However, because these compounds are all chemically related, they present similar liabilities in terms of target specificity and biopharmaceutical properties. Zenith Epigenetics is a biotechnology company with an expertise on the development of bromodomain inhibitors. To maintain their competitiveness, they must identify new targets and novel compounds that interact with them to modulate their activity. Recently, a new bromodomain containing protein (BCP) has been identified by Zenith Epigenetics, along with two molecules that bind to these proteins to interfere with their function. However, the chemical complexity of these compounds and the preparation of derivatives with increased potency requires an advanced expertise in organic synthesis and in medicinal chemistry. The goal of this project is to design and synthesize potent and selective inhibitors of BCPs that will serve as chemical probes to investigate the biochemical role of these proteins in chromatin remodeling and gene expression.**********