Selective Inhibition of Lysine‐Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple‐Negative Breast Cancer Therapy |
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| Authors: | Guan‐Jun Yang Wanhe Wang Dr. Simon Wing Fai Mok Chun Wu Betty Yuen Kwan Law Dr. Xiang‐Min Miao Ke‐Jia Wu Dr. Hai‐Jing Zhong Prof. Dr. Chun‐Yuen Wong Prof. Dr. Vincent Kam Wai Wong Prof. Dr. Dik‐Lung Ma Prof. Dr. Chung‐Hang Leung |
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| Affiliation: | 1. 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. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, China;4. School of Life Science, Jiangsu Normal University, Xuzhou, P. R. China;5. Department of Chemistry, City University of Hong Kong, Hong Kong SAR, P. R. China |
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| 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. |
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| Keywords: | drug discovery epigenetics medicinal chemistry triple-negative breast cancer |
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