Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy.
Angew Chem Int Ed Engl
; 57(40): 13091-13095, 2018 10 01.
Article
em En
| MEDLINE
| ID: mdl-29968419
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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Ródio
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Complexos de Coordenação
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Proteína 2 de Ligação ao Retinoblastoma
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Neoplasias de Mama Triplo Negativas
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article