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

Zonglong Chen; Jiayi Li; Hong Yang; Yulong He; Qiongyu Shi; Qi Chang; Ruiqi Liu; Xun Huang; Yingxia Li

doi:10.1016/j.bmc.2022.116784

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

Bioorg Med Chem. 2022 Jul 15:66:116784. doi: 10.1016/j.bmc.2022.116784. Epub 2022 May 1.

Authors

Zonglong Chen¹, Jiayi Li², Hong Yang³, Yulong He¹, Qiongyu Shi³, Qi Chang¹, Ruiqi Liu¹, Xun Huang⁴, Yingxia Li⁵

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
² School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
³ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁴ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.

PMID: 35569250
DOI: 10.1016/j.bmc.2022.116784

Abstract

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 (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.

Keywords: Bromodomain inhibitors; CBP30; P300; SBDD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis*
Benzimidazoles / pharmacology
Humans
Neoplasms*
Protein Domains

Substances

Benzimidazoles