Bromodomain-containing protein 4 belongs to the family of bromodomain and extra-terminal domain (BET) proteins. The BET family is considered as the most druggable target proteins among Bromodomain-containing proteins (BCPs) for regulating cellular epigenetics. Based on the diverse structures, currently available BET inhibitors under the investigation can be classified as azepines, quinazolin-4(3H)-one, pyridones, 3,5- dimethylisoxazoles, tetrahydroquinolines, 4-acylpyrroles, and others. Nevertheless, none of these compounds have yet been approved by FDA. Meanwhile, most of them are pan-BET inhibitors lacking selectivity for individual BET family members. Developing potent and highly selective BRD4 inhibitors for more applications is in an urgent need.

ZL0420 is more potent and selective than known inhibitors (+)-JQ1 and RVX-208. It is capable of significantly blocking the TLR3-dependent expression of innate immune genes ISG54, ISG56, IL-8, and Grob in hSAECs. ZL0420 displays nanomolar binding affinities for BDs of BRD4 protein with good selectivity over that of related BRD2 homolog. Molecular docking revealed their classical binding modes with the critical interactions identified between the ligand and the target protein. Further more, ZL0420 demonstrated potent efficacy reducing airway inflammation in a mouse model with low toxicity. ZL0420 displays high efficacy and almost completely blocks the profound accumulation of neutrophils around the small and medium sized airways induced by poly(I:C) administration.

To conclude, ZL0420 is a high potent BRD4 inhibitor with potential to treat airway infection.