Discovery of BET specific bromodomain inhibitors with a novel scaffold.

Bromodomain and extra-terminal domain (BET) proteins have been considered as potent candidates for anti-cancer drug development. As epigenetic readers, they modulate gene expression by recognizing acetylated lysine residues on histones. Therefore, the pharmacological inhibition of BET proteins has been extensively studied. Herein, we report the novel chemical scaffold of N-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazol-5-amine as BET inhibitors using high-throughput screening assay. Through the analysis of structure-activity relationships, we developed a potent novel compound, which exhibited a better IC50 value about 2-fold compared to iBet762 against the BRD4 bromodomain (BD). The addition of a sulfonyl group to the pyridine ring enhanced the inhibitory activity. Structural studies showed a clear electron density map for the inhibitor and revealed the structural basis for the critical role of the sulfonyl group in the interaction with BRD4.