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

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.

• Authors: 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, Dik-Lung Ma, Chung-Hang Leung
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 57 Issue 40 Pg. 13091-13095 (10 01 2018) ISSN: 1521-3773 [Electronic] Germany
• PMID: 29968419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Histones
• Iridium
• Rhodium
• KDM5A protein, human
• Retinoblastoma-Binding Protein 2

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use, toxicity)
• Cell Line, Tumor
• Cell Survival
• Coordination Complexes (chemistry, therapeutic use, toxicity)
• Female
• Histones (antagonists & inhibitors, metabolism)
• Humans
• Iridium (chemistry)
• Mice
• Mice, Inbred BALB C
• Retinoblastoma-Binding Protein 2 (antagonists & inhibitors, metabolism)
• Rhodium (chemistry)
• Transplantation, Heterologous
• Triple Negative Breast Neoplasms (drug therapy, pathology)