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Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy
Yang, Guan-Jun1; Wang, Wanhe2; Mok, Simon Wing Fai1; Wu, Chun2; Law, Betty Yuen Kwan1; Miao, Xiang-Min3; Wu, Ke-Jia1; Zhong, Hai-Jing1; Wong, Chun-Yuen2; Wong, Vincent Kam Wai2; Ma, Dik-Lung2; Leung, Chung-Hang1
2018-10
Source PublicationANGEWANDTE CHEMIE-INTERNATIONAL EDITION
ISSN1433-7851
Volume57Issue:40Pages:13091-13095
Abstract

Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.

KeywordDrug Discovery Epigenetics Medicinal Chemistry Triple-negative Breast Cancer
DOI10.1002/anie.201807305
URLView the original
Indexed BySCI
Language英语
WOS Research AreaChemistry
WOS SubjectChemistry, Multidisciplinary
WOS IDWOS:000445445700013
PublisherWILEY-V C H VERLAG GMBH
The Source to ArticleWOS
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Cited Times [WOS]:36   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorWong, Vincent Kam Wai; Ma, Dik-Lung; Leung, Chung-Hang
Affiliation1.Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
2.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
3.School of Life Science, Jiangsu Normal University, Xuzhou, P. R. China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Yang, Guan-Jun,Wang, Wanhe,Mok, Simon Wing Fai,et al. Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2018,57(40):13091-13095.
APA Yang, Guan-Jun.,Wang, Wanhe.,Mok, Simon Wing Fai.,Wu, Chun.,Law, Betty Yuen Kwan.,...&Leung, Chung-Hang.(2018).Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,57(40),13091-13095.
MLA Yang, Guan-Jun,et al."Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 57.40(2018):13091-13095.
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