Document Type

Journal Article

Department/Unit

Department of Chemistry

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.

Publication Year

2016

Journal Title

Oncotarget

Volume number

7

Issue number

12

Publisher

Impact Journals

First Page (page number)

13965

Last Page (page number)

13975

Referreed

1

DOI

10.18632/oncotarget.7369

Link to Publisher’s Edition

http://dx.doi.org/10.18632/oncotarget.7369

Keywords

metal-based inhibitor, protein-protein interaction, p53, hDM2

Additional Files

JA-5034-28962_publisher_suppl.pdf (4205 kB)

Included in

Chemistry Commons

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