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Selective Inhibition of Lysine‐Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple‐Negative Breast Cancer Therapy
Author(s) -
Yang GuanJun,
Wang Wanhe,
Mok Simon Wing Fai,
Wu Chun,
Law Betty Yuen Kwan,
Miao XiangMin,
Wu KeJia,
Zhong HaiJing,
Wong ChunYuen,
Wong Vincent Kam Wai,
Ma DikLung,
Leung ChungHang
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201807305
Subject(s) - demethylase , h3k4me3 , triple negative breast cancer , cancer research , epigenetics , chemistry , lysine , epigenetic therapy , cancer , biology , biochemistry , breast cancer , gene , gene expression , amino acid , dna methylation , genetics , promoter
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.