Bromodomains are a family of epigenetic reader domains which recognize acetylated histone lysine residues, recruiting transcription factors to specific DNA locales. Aberrant bromodomain function is strongly implicated in a wide variety of diseases. Bromodomains are amenable to small-molecule inhibition, but in many cases either no inhibitor is known or a published inhibitor is only weakly selective. The bromodomain and extra-terminal domain (BET) family of proteins are strongly linked to diverse cancers, autoimmune inflammation and other diseases, with several BET inhibitors in clinical trials. The BET family contains four proteins, Brd2, 3, 4, and T, which each contain two bromodomains, BD1 and BD2. BD2-selective BET inhibitors have received little attention, hindering the elucidation of the biological roles of the BD2 domains. This work set out to develop potent BD2-selective BET inhibitors with drug-like properties. Using a strategy of late-stage synthetic diversity, parallel vector exploration, and structure- and knowledge-based optimisation, diverse analogues were synthesised and screened. The structure-activity relationships (SARs) of the template were elucidated, and the binding mode and selectivity rationale were determined through X-ray crystallography. This optimisation resulted in low-nanomolar, cell potent BD2 inhibitors with excellent wider bromodomain selectivity and good drug-like properties, suitable for use as in vitro or in vivo tools for target validation.The function of the BRPF1 bromodomain is unknown, and while selective inhibitors have been developed their chemical diversity is poor. Starting from moderately potent but promiscuous hits, a structurally diverse series of BRPF1 inhibitors was investigated, aiming to improve potency and selectivity. Diverse, novel substitution patterns of the hit template and similar scaffolds were synthesised, investigated and SAR generated. Though increasing potency proved challenging, selectivity over other bromodomains was improved and the binding mode was elucidated through X-ray crystallography. This work has generated useful leads for further optimisation, thoroughly investigated the template and gained insights into BRPF1-ligand binding.
| Date of Award | 4 Mar 2016 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde & Glaxo Smithkline (UK) |
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