Discovery of novel benzimidazole derivatives as potent p300 bromodomain inhibitors with anti-proliferative activity in multiple cancer cells.

[Display omitted] • A series of p300 bromodomain inhibitors with new scaffolds was discovered based on bioisosterism and conformational restriction strategies. • Compounds 1u showed improved p300 bromodomain inhibitory activity and anti-proliferative activity in OPM-2 human myeloma cell line compared to CBP30. • Western blotting analysis showed that 1u suppressed the expression of c-Myc. • Mechanism studies indicated that 1u induced G 1 /G 0 phase arrest and apoptosis in OPM-2 cells. Adenovirus E1A-associated 300-k D protein (p300) bromodomain, which regulates gene expression by recognizing acetylated lysine (KAc) of histone, is a promising target for the treatment of cancer. Herein, a series of potent p300 bromodomain inhibitors with novel CBP30-based scaffolds was discovered through bioisosterism and conformational restriction strategies. The most promising compound 1u showed more potent inhibitory activity (IC 50 = 49 nM) against p300 bromodomain and anti-proliferative activity in various cancer cell lines compared to CBP30. Moreover, 1u suppressed the expression of c-Myc and induced G 1 /G 0 phase arrest and apoptosis in OPM-2 cells more potently than CBP30. This study provides new lead compounds for further research on the biological functions of p300. [ABSTRACT FROM AUTHOR]