DW71177: A novel [1,2,4]triazolo[4,3-a]quinoxaline-based potent and BD1-Selective BET inhibitor for the treatment of acute myeloid leukemia
The bromodomain and extraterminal domain (BET) family of proteins play a crucial role in regulating gene expression by recognizing acetyl-lysine (Kac) residues on histone tails through their two tandem bromodomains, BD1 and BD2. Due to their involvement in oncogenic transcriptional activation, BET proteins are considered promising therapeutic targets in cancer treatment, as bromodomains have well-defined Kac-binding pockets.
In this study, we introduce DW-71177, a potent BET inhibitor that selectively binds to BD1 and demonstrates strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamics studies confirm the robust and specific binding of DW-71177 to the Kac-binding pocket of BD1. This compound effectively inhibits oncogenes similarly to the pan-BET inhibitor OTX-015, while having a lesser impact on housekeeping genes. DW-71177 efficiently disrupts cancer-related transcriptional changes by targeting genes enriched with BRD4 and histone acetylation marks. These findings suggest that selectively targeting BD1 could be an effective and safer therapeutic strategy for treating leukemia.