Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy

Guan Jun Yang, Wanhe Wang, Simon Wing Fai Mok, Chun Wu, Betty Yuen Kwan Law, Xiang Min Miao, Ke Jia Wu, Hai Jing Zhong, Chun Yuen Wong, Vincent Kam Wai Wong*, Edmond Dik Lung MA, Chung Hang Leung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13091-13095
Number of pages5
JournalAngewandte Chemie. International Edition
Volume57
Issue number40
DOIs
Publication statusPublished - 1 Oct 2018

Scopus Subject Areas

  • Catalysis
  • Chemistry(all)

User-Defined Keywords

  • drug discovery
  • epigenetics
  • medicinal chemistry
  • triple-negative breast cancer

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