2. Academic Validation
  3. Discovery of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as novel and potent bromodomain and extra-terminal (BET) inhibitors with anticancer efficacy

Discovery of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as novel and potent bromodomain and extra-terminal (BET) inhibitors with anticancer efficacy

  • Eur J Med Chem. 2022 Jan 5:227:113953. doi: 10.1016/j.ejmech.2021.113953.
Bo Kong 1,  Zhaohong Zhu 1,  Hongmei Li 1,  Qianqian Hong 1,  Cong Wang 1,  Yu Ma 1,  Wan Zheng 2,  Fei Jiang 1,  Zhimin Zhang 1,  Ting Ran 1,  Yuanyuan Bian 1,  Na Yang 1,  Tao Lu 3,  Jiapeng Zhu 4,  Weifang Tang 5,  Yadong Chen 6
Affiliations

Affiliations

  • 1 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2 School of Medicine & Holistic Integrative Medicine, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 3 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 4 School of Medicine & Holistic Integrative Medicine, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: zhujiapeng@hotmail.com.
  • 5 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: twf@cpu.edu.cn.
  • 6 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: ydchen@cpu.edu.cn.
PMID: 34731760 DOI: 10.1016/j.ejmech.2021.113953
Abstract

As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for Cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G0/G1 phase and induce Apoptosis via decreasing the expression of c-Myc and Other proteins related to cell cycle and Apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors.

Keywords

1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives; BET inhibitor; Hematologic malignancies; Solid tumors.

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