Developing small molecule inhibitors of bromodomain-histone interactions

• Main Author: Wilson, Brian Gerald
• Other Authors: Conway, Stuart ; Reuberson, James
• Published: University of Oxford 2015
• Subjects: 572
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.712444

Bromodomains, protein modules found in 46 human chromatin-associated proteins, bind to acetylated lysine residues (KAc), and modulate the formation of complex protein scaffolds, which are often involved in transcription. The work in this dissertation focuses on the development of small molecule inhibitors for the BRD9 bromodomain, which is a component of nucleosome remodelling complexes, and has been linked to lung and cervical cancers. The lead molecule was based on the triazole KAc mimic, which is a promiscuous bromodomain ligand. Using a rational approach involving evaluation at the four positions shown on scaffold 1, this work led to compound 2, which has nanomolar affinity for the BRD9 bromodomain, and some selectivity over BRD4(1). Compound 2 was shown to have a high lipophilic ligand efficiency, high aqueous solubility, and moderate metabolic stability in an in vitro mouse model, making it suitable for further studies in a biological setting. Microscale Thermophoresis has been used as a new technique to measure interactions between small molecule ligands and their bromodomain binding partners. This work has provided useful structure-activity relationships for a subset of bromodomains, which will be useful in future ligand development programmes of this emerging therapeutic target class.