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Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds.
- Source :
-
Oncotarget [Oncotarget] 2016 Mar 22; Vol. 7 (12), pp. 13965-75. - Publication Year :
- 2016
-
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.
- Subjects :
- Antineoplastic Agents chemistry
Apoptosis drug effects
Humans
Iridium chemistry
Neoplasms metabolism
Neoplasms pathology
Organometallic Compounds chemistry
Protein Interaction Domains and Motifs drug effects
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Cells, Cultured
Tumor Suppressor Protein p53 metabolism
Antineoplastic Agents pharmacology
Cell Proliferation drug effects
Iridium pharmacology
Neoplasms drug therapy
Organometallic Compounds pharmacology
Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
Tumor Suppressor Protein p53 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26883110
- Full Text :
- https://doi.org/10.18632/oncotarget.7369