Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation

Bromodomain-containing protein 4
(BRD4) represents a promising
drug target for anti-inflammatory therapeutics. Herein, we report
the design, synthesis, and pharmacological evaluation of novel chromone
derivatives via scaffold hopping to discover a new class of orally
bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain
1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67–84 nM) and good selectivity over other
BRD family proteins and distant BD-containing proteins. Both compounds
significantly inhibited the expression of Toll-like receptor-induced
inflammatory genes in vitro and airway inflammation in murine models.
The cocrystal structure of 45 in complex with human BRD4
BD1 at a high resolution of 2.0 Å has been solved, offering a
solid structural basis for its binding validation and further structure-based
optimization. These BRD4 BD1 inhibitors demonstrated impressive in
vivo efficacy and overall promising pharmacokinetic properties, indicating
their therapeutic potential for the treatment of inflammatory diseases.