BET inhibitors(The University of Nottingham)

BET bromodomain inhibitors demonstrate significant promise as anti-inflammatory agents. However, clinical data demonstrated that nonselective BET bromodomain inhibitors led to significant dose-limiting toxicity in clinical settings. Here, we use three orally bioavailable inhibitors, 1-3, that are either BRD4-D1 selective or pan-D1-biased + BRD4-D2, for assessing their cellular and in vivo efficacy and safety profile compared to known BET inhibitors in two inflammatory disease models. Our results show that pan-D1-biased + BRD4-D2 inhibitor, 3, is as efficacious as pan-BET inhibitor, I-BET151, in reducing inflammation in both models, whereas pan-D2 inhibitors are less effective. BRD4-D1 selective inhibitors are also efficacious; however, inhibitors with improved cellular engagement will be necessary to better assess their effects. Finally, BRD4-D1 selective inhibitors are better tolerated in a preclinical thrombocytopenia model than 3, while gastrointestinal toxicity may be a BRD4-driven effect. These results highlight the importance of assessing specific BET bromodomain functions due to their diverse roles in disease models.

The bromodomain and extra-terminal domain (BET) protein family is a class of epigenetic reader proteins that recognize N-acetylated lysine residues in histone tails, playing a crucial role in gene expression and cell transcription. Selective inhibition of bromodomain-containing proteins (BRDs) disrupts transcription in key oncogenes. Over the past decade there has been considerable interest in developing small molecule BET inhibitors for the treatment of hematological malignancies and solid tumors. Herein, we report the development of a triazinoindole scaffold capable of the inhibition of bromodomain-containing protein 4 (BRD4), with either dimethylisoxazole or dimethyltriazole substituents acting as chemomimetics of the N-acetylated lysine residues. Derivatization of the parent scaffold afforded the lead compound, which displays low nanomolar affinity toward BRD4-BD1 with a favorable physicochemical and in vitro stability profile.