Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds

Li Juan Liu, Bingyong He, Jennifer A. Miles, Wanhe Wang, Zhifeng Mao, Weng Ian Che, Jin Jian Lu, Xiu Ping Chen, Andrew J. Wilson, Edmond Dik Lung MA, Chung Hang Leung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)13965-13975
Number of pages11
JournalOncotarget
Volume7
Issue number12
DOIs
Publication statusPublished - 22 Mar 2016

Scopus Subject Areas

  • Oncology

User-Defined Keywords

  • HDM2
  • Metal-based inhibitor
  • P53
  • Protein-protein interaction

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