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An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells
Yang, Guan Jun1; Song, Ying Qi1; Wang, Wanhe2; Han, Quan Bin3; Ma, Dik Lung2; Leung, Chung Hang1,4
2021-09-01
Source PublicationBioorganic Chemistry
ISSN0045-2068
Volume114
Abstract

Acetylation of NF-κB's RelA subunit at lysine-310 (AcLys310) helps to maintain constitutive NF-κB activity in cancers such as triple-negative breast cancer (TNBC). Bromodomain-containing factor BRD4 binds to acetylated RelA to promote the activity of NF-κB. Hence, interfering with the acetylated RelA-BRD4 interaction is a potential strategy for treating NF-κB-driven TNBC. Here, a new compound 13a was obtained by structural optimization and modification of our previously reported compound. In comparison with the well-known BRD4 inhibitor (+)-JQ1, 13a showed more potent anticancer activity in NF-κB-active MDA-MB-231 cells. Mechanistically, 13a antagonized the protein–protein interaction (PPI) between BRD4 and acetylated RelA, decreased levels of IL-6, IL-8, Snail, Vimentin, and ZEB1, induced cell senescence and DNA damage, and weakened the adhesion, metastasis, and invasion ability of TNBC cells. Our results provide insights into avenues for the further development of potent BRD4-acetylated RelA PPI inhibitors. Moreover, our findings highlight the effectiveness and feasibility of blocking the interaction between BRD4 and acetylated RelA against NF-κB-active cancers, and of screening antagonists of this PPI.

KeywordAcetylated Rela Brd4 Nf-κb Protein-protein Interaction Tnbc
DOI10.1016/j.bioorg.2021.105158
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaBiochemistry & Molecular Biology ; Chemistry
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Organic
WOS IDWOS:000691057700002
Scopus ID2-s2.0-85110065676
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Cited Times [WOS]:7   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macao
2.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, 999077, Hong Kong
3.School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, 999077, Hong Kong
4.Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, 999078, Macao
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Yang, Guan Jun,Song, Ying Qi,Wang, Wanhe,et al. An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells[J]. Bioorganic Chemistry,2021,114.
APA Yang, Guan Jun,Song, Ying Qi,Wang, Wanhe,Han, Quan Bin,Ma, Dik Lung,&Leung, Chung Hang.(2021).An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells.Bioorganic Chemistry,114.
MLA Yang, Guan Jun,et al."An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells".Bioorganic Chemistry 114(2021).
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