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

• Published in: Bioorganic & medicinal chemistry 2022-07, Vol.66, p.116784-116784, Article 116784
• Main Authors: Chen, Zonglong, Li, Jiayi, Yang, Hong, He, Yulong, Shi, Qiongyu, Chang, Qi, Liu, Ruiqi, Huang, Xun, Li, Yingxia
• Format: Article
• Language: English
• Subjects: Bromodomain inhibitors; CBP30; P300; SBDD
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.116784

[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 G1/G0 phase arrest and apoptosis in OPM-2 cells. Adenovirus E1A-associated 300-kD 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 (IC50 = 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 G1/G0 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.