Efficacy and Toxicity Analysis of Selective BET Bromodomain Inhibitors in Models of Inflammatory Liver Disease

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.