Angewandte Chemie International Edition, 2018-10, Vol.57 (40), p.13091-13095
International ed. in English, 2018
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- Autor(en) / Beteiligte
- Titel
- Selective Inhibition of Lysine‐Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple‐Negative Breast Cancer Therapy
- Ist Teil von
- Angewandte Chemie International Edition, 2018-10, Vol.57 (40), p.13091-13095
- Auflage
- International ed. in English
- Ort / Verlag
- Germany: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. A rhodium(III)‐based complex has been discovered as an inhibitor of KDM5A, an epigenetic target for triple‐negative breast cancer. The complex inhibited the KDM5A–H3K4me3 interaction and suppressed proliferation of triple‐negative breast cancer (TNBC) tumors in mice and may be used as a novel scaffold for further development of more potent epigenetic agents against cancers, including TNBC.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1433-7851eISSN: 1521-3773DOI: 10.1002/anie.201807305Titel-ID: cdi_proquest_journals_2111555685
- Format
- –
- Schlagworte
- Animals, Antineoplastic Agents - chemistry, Antineoplastic Agents - therapeutic use, Antineoplastic Agents - toxicity, Biocompatibility, Breast cancer, Cancer, Cancer therapies, Cell Line, Tumor, Cell Survival, Cisplatin, Coordination Complexes - chemistry, Coordination Complexes - therapeutic use, Coordination Complexes - toxicity, Coordination compounds, Doxorubicin, drug discovery, Epigenetics, Female, G1 phase, Histones - antagonists & inhibitors, Histones - metabolism, Humans, Inhibitors, Iridium - chemistry, Lysine, medicinal chemistry, Metal complexes, Mice, Mice, Inbred BALB C, Proteins, Retinoblastoma-Binding Protein 2 - antagonists & inhibitors, Retinoblastoma-Binding Protein 2 - metabolism, Rhodium, Rhodium - chemistry, Therapy, Transplantation, Heterologous, Triple Negative Breast Neoplasms - drug therapy, Triple Negative Breast Neoplasms - pathology, triple-negative breast cancer, Tumor cell lines, Xenografts, Xenotransplantation