A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 and ZL0454 were identified as potent and specific BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4 with high selectivity over other BET proteins. Both of them can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H<sub>2</sub>O molecule. Both ZL0420 and ZL0454 exhibited submicromolar potency of inhibiting the TLR3-dependent innate immune gene program, including ISG54, ISG56, IL-8, and Groβ genes in cultured human small airway epithelial cells (hSAECs). More importantly, they also demonstrated potent efficacy reducing airway inflammation in a mouse model, indicating a proof of concept that BRD4 inhibitors may offer the therapeutic potential to block the viral-induced airway inflammation.

Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation

256th National Meeting (2018)

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