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  3. Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer

Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer

  • Eur J Med Chem. 2024 Jan 6:266:116116. doi: 10.1016/j.ejmech.2023.116116.
Ruizhi Lai 1,  Zhiqian Lin 1,  Chunyan Yang 1,  Li Hai 2,  Zhongzhen Yang 1,  Li Guo 1,  Ruifang Nie 3,  Yong Wu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 2 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China; Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, 646100, China.
  • 3 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250000, China. Electronic address: ruifangnie@163.com.
  • 4 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: wyong@scu.edu.cn.
PMID: 38215590 DOI: 10.1016/j.ejmech.2023.116116
Abstract

Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in Epigenetics, participating in numerous cellular pathways including proliferation, differentiation and Apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show Anticancer activity and synergistic effect in combination with some of the clinical Anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast Cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC50 values of 1.51 μM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo.

Keywords

Cancer therapy; Combination treatment; Histone acetyltransferase; Small-molecule inhibitor; p300/CBP.

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