Department of Chemistry
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.
metal-based inhibitor, protein-protein interaction, p53, hDM2
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Liu, L., He, B., Miles, J., Wang, W., Mao, Z., Che, W., Lu, J., Chen, X., Wilson, A., Ma, D., & Leung, C. (2016). Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds. Oncotarget, 7 (12). https://doi.org/10.18632/oncotarget.7369