Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds

Li Juan Liu; Bingyong He; Jennifer A. Miles; Wanhe Wang; Zhifeng Mao; Weng Ian Che; Jin Jian Lu; Xiu Ping Chen; Andrew J. Wilson; Dik Lung Ma; Chung Hang Leung

doi:10.18632/oncotarget.7369

Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds

Li Juan Liu, Bingyong He, Jennifer A. Miles, Wanhe Wang, Zhifeng Mao, Weng Ian Che, Jin Jian Lu, Xiu Ping Chen, Andrew J. Wilson, Dik Lung Ma, Chung Hang Leung^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

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.

Original language	English
Pages (from-to)	13965-13975
Number of pages	11
Journal	OncoTarget
Volume	7
Issue number	12
DOIs	https://doi.org/10.18632/oncotarget.7369
Publication status	Published - 22 Mar 2016

Bibliographical note

Funding Information:
This work is supported by Hong Kong Baptist University (FRG2/14-15/004), the Health and Medical Research Fund (HMRF/13121482 and HMRF/14130522), the Research Grants Council (HKBU/201913), National Natural Science Foundation of China (21575121), Guangdong Province Natural Science Foundation (2015A030313816), Hong Kong Baptist University Century Club Sponsorship Scheme 2015, the European Research Council [ERC-StG-240324] and [ERC-PoC 632207], the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12; Oligoswitch ANR-12-IS07-0001), Interdisciplinary Research Matching Scheme (RC-IRMS/14-15/06), the Science and Technology Development Fund, Macao SAR (103/2012/A3), the University of Macau (MYRG2015-00137-ICMS-QRCM, MRG023/LCH/2013/ICMS and MRG044/LCH/2015/ICMS).

Keywords

HDM2
Metal-based inhibitor
P53
Protein-protein interaction

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.7369

Cite this

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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.",

keywords = "HDM2, Metal-based inhibitor, P53, Protein-protein interaction",

author = "Liu, {Li Juan} and Bingyong He and Miles, {Jennifer A.} and Wanhe Wang and Zhifeng Mao and Che, {Weng Ian} and Lu, {Jin Jian} and Chen, {Xiu Ping} and Wilson, {Andrew J.} and Ma, {Dik Lung} and Leung, {Chung Hang}",

note = "Funding Information: This work is supported by Hong Kong Baptist University (FRG2/14-15/004), the Health and Medical Research Fund (HMRF/13121482 and HMRF/14130522), the Research Grants Council (HKBU/201913), National Natural Science Foundation of China (21575121), Guangdong Province Natural Science Foundation (2015A030313816), Hong Kong Baptist University Century Club Sponsorship Scheme 2015, the European Research Council [ERC-StG-240324] and [ERC-PoC 632207], the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12; Oligoswitch ANR-12-IS07-0001), Interdisciplinary Research Matching Scheme (RC-IRMS/14-15/06), the Science and Technology Development Fund, Macao SAR (103/2012/A3), the University of Macau (MYRG2015-00137-ICMS-QRCM, MRG023/LCH/2013/ICMS and MRG044/LCH/2015/ICMS).",

year = "2016",

month = mar,

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doi = "10.18632/oncotarget.7369",

language = "English",

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AU - He, Bingyong

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AU - Mao, Zhifeng

AU - Che, Weng Ian

AU - Lu, Jin Jian

AU - Chen, Xiu Ping

AU - Wilson, Andrew J.

AU - Ma, Dik Lung

AU - Leung, Chung Hang

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N2 - 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.

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SN - 1949-2553

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ER -

Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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