Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 24, Pages 18025-18053Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01382
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Funding
- National Natural Science Foundation of China [81922064, 81874290, 81903502, 81803365]
- Applied Basic Research Programs of Science and Technology Department of Sichuan Province [2020YJ0105, 2020YJ0094]
- Fundamental Research Funds for the Central Universities [2021SCU12102]
- China Postdoctoral Science Foundation [2020M673268]
- Health Commission of Sichuan Province [20PJ002]
- U.S. National Institutes of Health [1RO1CA251698-01]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP180349, RP190077]
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The study synthesized a potent BRD4-CK2 dual inhibitor, which showed strong anti-proliferative effects and induced apoptosis and autophagy-related cell death in tumor cells. It has potential therapeutic value for triple-negative breast cancer.
Bromodomain-containing protein 4 (BRD4) is an attractive epigenetic target in human cancers. Inhibiting the phosphorylation of BRD4 by casein kinase 2 (CK2) is a potential strategy to overcome drug resistance in cancer therapy. The present study describes the synthesis of multiple BRD4-CK2 dual inhibitors based on rational drug design, structure-activity relationship, and in vitro and in vivo evaluations, and 44e was identified to possess potent and balanced activities against BRD4 (IC50 = 180 nM) and CK2 (IC50 = 230 nM). In vitro experiments show that 44e could inhibit the proliferation and induce apoptosis and autophagy-associated cell death of MDA-MB-231 and MDAMB-468 cells. In two in vivo xenograft mouse models, 44e displays potent anticancer activity without obvious toxicities. Taken together, we successfully synthesized the first highly effective BRD4-CK2 dual inhibitor, which is expected to be an attractive therapeutic strategy for triple-negative breast cancer (TNBC).
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