期刊
CHEMICAL SCIENCE
卷 6, 期 10, 页码 5400-5408出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5sc02321a
关键词
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资金
- Hong Kong Baptist University [FRG2/14-15/004]
- Health and Medical Research Fund [HMRF/13121482, HMRF/14130522]
- Research Grants Council [HKBU/201811, HKBU/204612, HKBU/201913]
- French National Research Agency/Research Grants Council Joint Research Scheme [A-HKBU201/12]
- Interdisciplinary Research Matching Scheme [RC-IRMS/14-15/06]
- Science and Technology Development Fund, Macao SAR [103/2012/A3, 098/2014/A2]
- University of Macau [MYRG091(Y3-L2)-ICMS12-LCH, MYRG2015-00137-ICMS-QRCM, MRG023/LCH/2013/ICMS]
- National Science Council [NSC102-2622-E-037-002, NSC102-2221-E-037-005, NSC102-2622-E-011-001-CC2, MOST103-2221-E-037-004]
- Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU)
Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(III) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex 1a is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI) in vitro, and to bind BRD4 and down-regulate c-myc oncogenic expression in cellulo. Chromatin immunoprecipitation (ChIP) analysis revealed that 1a could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an in vivo mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex 1a may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.
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