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Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds
- Source :
- Oncotarget
- Publication Year :
- 2016
- Publisher :
- Impact Journals, LLC, 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 :
- p53
Stereochemistry
Antineoplastic Agents
Apoptosis
Iridium
010402 general chemistry
medicine.disease_cause
01 natural sciences
Protein–protein interaction
protein-protein interaction
Ubiquitin
Proto-Oncogene Proteins c-mdm2
Neoplasms
Organometallic Compounds
Tumor Cells, Cultured
medicine
Humans
Protein Interaction Domains and Motifs
Transcription factor
Cell Proliferation
Mutation
biology
010405 organic chemistry
Cell growth
Chemistry
hDM2
metal-based inhibitor
3. Good health
0104 chemical sciences
Ubiquitin ligase
Oncology
Biochemistry
biology.protein
Tumor Suppressor Protein p53
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....7bd6140d43955765e1df219ab2632da7