Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N‑Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype

The
bromodomain and extraterminal 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, the development of inhibitors selective for
individual, or sets of, bromodomains within the family is required.
In this regard, we report the discovery of a potent probe molecule
possessing up to 150-fold selectivity for the N-terminal bromodomains
(BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided
by structural information, a specific amino acid difference between
BD1 and BD2 domains was targeted for selective interaction with chemical
functionality appended to the previously developed I-BET151 scaffold.
Data presented herein demonstrate that selective inhibition of BD1
domains is sufficient to drive anti-inflammatory and antiproliferative
effects.