Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 40, Pages 13091-13095Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201807305
Keywords
drug discovery; epigenetics; medicinal chemistry; triple-negative breast cancer
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Funding
- Hong Kong Baptist University [FRG2/16-17/007, FRG2/17-18/003]
- Health and Medical Research Fund [HMRF/14150561]
- Research Grants Council [HKBU/12301115, CityU/11228316, CityU/11207117]
- National Natural Science Foundation of China [21575121, 21628502, 21775131]
- Guangdong Province Natural Science Foundation [2015A030313816]
- Hong Kong Baptist University Century Club Sponsorship Scheme 2017
- Interdisciplinary Research Matching Scheme [RC-IRMS/15-16/03, RC-IRMS/16-17/03]
- Innovation and Technology Fund [ITS/260/16FX]
- Collaborative Research Fund [C5026-16G]
- Matching Proof of Concept Fund [MPCF-001-2017/18]
- Science and Technology Development Fund, Macao SAR [077/2016/A2]
- University of Macau [MYRG2016-00151-ICMS-QRCM]
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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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