Background: The bromodomain and extra-terminal proteins (BET), in particular BRD4,
has recently emerged as a potential therapeutic target for the treatment of many human disorders
such as cancer, inflammation, obesity and cardiovascular disease, which draw more and more
attention to discover potent BRD4 inhibitors in the past years. In this article, we described the
discovery process of an entirely new chemotype of BRD4 inhibitors.
Methods: A fragment-based drug discovery strategy was employed in attempting to find a novel
chemotype of BRD4 inhibitors. Thus, the potential hits were firstly identified by docking study with
KAc binding pocket and AlphaScreen assay. Then the elected hit was further structurally optimized
based on the interaction revealed by the docking study and the Structure-Activity Relationship
Results: A 1-(2-hydroxyphenyl)ethan-1-one fragment was first identified as an efficient hit to BRD4
with a weak inhibition activity and high ligand efficiency (IC50 = 8.9 μM, LE > 0.5) based on
virtual screening and biochemical assay. Then, two-rounds optimization of the hit by a fragmentbased
drug discovery approach enabled the discovery of a potent BRD4 inhibitor 9, which exhibit
nanomolar potency in biochemical assays (IC50 = 0.18 μM).
Conclusion: The title compounds displayed potent inhibitory activity to BRD4, implying
acetophenone core is an effective KAc residue mimic, suggesting acetophenone derivatives as a new
chemotype may be promising for developing novel BRD4 inhibitors.