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

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.

• Authors: Li-Juan Liu, Bingyong He, Jennifer A Miles, Wanhe Wang, Zhifeng Mao, Weng Ian Che, Jin-Jian Lu, Xiu-Ping Chen, Andrew J Wilson, Dik-Lung Ma, Chung-Hang Leung
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 12 Pg. 13965-75 (Mar 22 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26883110 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• TP53 protein, human
• Tumor Suppressor Protein p53
• Iridium
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Humans
• Iridium (chemistry, pharmacology)
• Neoplasms (drug therapy, metabolism, pathology)
• Organometallic Compounds (chemistry, pharmacology)
• Protein Interaction Domains and Motifs (drug effects)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (antagonists & inhibitors, metabolism)