title: Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds.
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.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Bingyong
authors.initials: B
authors.lastname: He
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.|Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Miles
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Wanhe
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Weng Ian
authors.initials: WI
authors.lastname: Che
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Jin-Jian
authors.initials: JJ
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Xiu-Ping
authors.initials: XP
authors.lastname: Chen
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.|Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007495:Iridium; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: hDM2; metal-based inhibitor; p53; protein-protein interaction