Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds
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Li-Juan Liu1, Bingyong He2, Jennifer A. Miles3,4, Wanhe Wang2, Zhifeng Mao2, Weng Ian Che1, Jin-Jian Lu1, Xiu-Ping Chen1, Andrew J. Wilson3,4, Dik-Lung Ma2, Chung-Hang Leung1
1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
3School of Chemistry, University of Leeds, Leeds, UK
4Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
Chung-Hang Leung, e-mail: [email protected]
Dik-Lung Ma, e-mail: [email protected]
Keywords: metal-based inhibitor, protein-protein interaction, p53, hDM2
Received: October 23, 2015 Accepted: January 29, 2016 Published: February 13, 2016
Inactivation of the p53 transcription factor by mutation or other mechanisms is a frequent event in tumorigenesis. One of the major endogenous negative regulators of p53 in humans is hDM2, a ubiquitin E3 ligase that binds to p53 causing proteasomal p53 degradation. In this work, a library of organometallic iridium(III) compounds were synthesized and evaluated for their ability to disrupt the p53/hDM2 protein-protein interaction. The novel cyclometallated iridium(III) compound 1 [Ir(eppy)2(dcphen)](PF6) (where eppy = 2-(4-ethylphenyl)pyridine and dcphen = 4, 7-dichloro-1, 10-phenanthroline) blocked the interaction of p53/hDM2 in human amelanotic melanoma cells. Finally, 1 exhibited anti-proliferative activity and induced apoptosis in cancer cell lines consistent with inhibition of the p53/hDM2 interaction. Compound 1 represents the first reported organometallic p53/hDM2 protein-protein interaction inhibitor.
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