The bromodomain and extra terminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT) each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, this presentation describes the discovery of imidazoquinoline <b>1</b>, a potent probe molecule possessing up to 200-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of BET. Guided by structural information, a specific residue difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Subsequent modification of the imidazoquinolinone scaffold resulted in imidazoquinoline<b> 1</b> which demonstrated sufficient exposure in vivo to be capable of engaging BD1 domains while minimizing interaction at BD2 domains. Data presented here demonstrates that selective inhibition of BD1 domains is sufficient to drive antiproliferative effects.

Structure-based design of an N-terminal bromodomain selective bromodomain and extraterminal (BET) inhibitor retaining an antiproliferative phenotype

2019 Fall National Meeting

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