This thesis describes the design and synthesis of chemical probes for non-BET bromodomains.Studies have shown that inhibition of the BET bromodomains leads to profound activity in immuno-inflammation and oncology disease settings, with several BET bromodomain inhibitors entering the clinic. The validation of this new target class has led to a surge of interest in the remaining 53 non-BET bromodomains. Whilst the majority of non-BET bromodomains have been implicated in disease pathways, the biological role they play in mediating disease states is unknown. To help delineate the function of the non-BET bromodomains in disease, and establish their potential as therapeutic targets, academia and industry have begun developing chemical probes for their preclinical target validation.A chemical probe for the TAF1/TAF1L bromodomains was designed from a naphthyridinone scaffold. Statistical analysis was used to establish a relationship between permeability and pKa and, in turn, guide the optimization of permeability on the series. The developed probe molecule shows excellent potency (TAF1(2) pKD = 9.1), selectivity over the BET bromodomains (1000-fold) and other non-BET bromodomains where tested (≥50-fold), improved permeability (62 nm/s), and represents a novel chemotype for TAF1/TAF1L inhibitors. From here, the concept of conserved water interactions was explored in an attempt to further increase non-BET bromodomain selectivity for TAF1(2).A BRD7/9 template was then selected to explore the concept of bromodomain selectivity through conserved water interactions more extensively. A novel butyl acetylated Lys methyl mimetic motif was discovered and utilized to produce a selective BRD7/9 chemical probe with accompanying negative control. The broader applicability of the butyl motif was then demonstrated across a variety of scaffolds to enhance selectivity for BRD7/9 in a predictable manner.
| Date of Award | 13 May 2020 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | Nick Tomkinson (Supervisor) & Glenn Burley (Supervisor) |
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