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

• DOI: 10.18632/oncotarget.7369
• Publication Date: 2016-02-13T15:57:30Z
• 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
• Keywords: Antineoplastic Agents; Apoptosis; Proto-Oncogene Proteins c-mdm2; Iridium; 01 natural sciences; 0104 chemical sciences; 3. Good health; Neoplasms; Organometallic Compounds; Tumor Cells, Cultured; Humans; Protein Interaction Domains and Motifs; Tumor Suppressor Protein p53; Research Paper; Cell Proliferation

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.