A Metal-Based Inhibitor of NEDD8-Activating Enzyme

Hai Jing Zhong; Hui Yang; Daniel Shiu Hin Chan; Chung Hang Leung; Hui Min Wang; Dik Lung Ma

doi:10.1371/journal.pone.0049574

A Metal-Based Inhibitor of NEDD8-Activating Enzyme

Hai Jing Zhong, Hui Yang, Daniel Shiu Hin Chan, Chung Hang Leung, Hui Min Wang, Dik Lung Ma^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-review

42 Citations (Scopus)

Abstract

A cyclometallated rhodium(III) complex [Rh(ppy)₂(dppz)]⁺ (1) (where ppy = 2-phenylpyridine and dppz = dipyrido[3,2-a:2′,3′-c]phenazine dipyridophenazine) has been prepared and identified as an inhibitor of NEDD8-activating enzyme (NAE). The complex inhibited NAE activity in cell-free and cell-based assays, and suppressed the CRL-regulated substrate degradation and NF-κB activation in human cancer cells with potency comparable to known NAE inhibitor MLN4924. Molecular modeling analysis suggested that the overall binding mode of 1 within the binding pocket of the APPBP1/UBA3 heterodimer resembled that for MLN4924. Complex 1 is the first metal complex reported to suppress the NEDDylation pathway via inhibition of the NEDD8-activating enzyme.

Original language	English
Article number	e49574
Journal	PLoS ONE
Volume	7
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0049574
Publication status	Published - 19 Nov 2012

Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology
General Agricultural and Biological Sciences
General

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

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title = "A Metal-Based Inhibitor of NEDD8-Activating Enzyme",

abstract = "A cyclometallated rhodium(III) complex [Rh(ppy)2(dppz)]+ (1) (where ppy = 2-phenylpyridine and dppz = dipyrido[3,2-a:2′,3′-c]phenazine dipyridophenazine) has been prepared and identified as an inhibitor of NEDD8-activating enzyme (NAE). The complex inhibited NAE activity in cell-free and cell-based assays, and suppressed the CRL-regulated substrate degradation and NF-κB activation in human cancer cells with potency comparable to known NAE inhibitor MLN4924. Molecular modeling analysis suggested that the overall binding mode of 1 within the binding pocket of the APPBP1/UBA3 heterodimer resembled that for MLN4924. Complex 1 is the first metal complex reported to suppress the NEDDylation pathway via inhibition of the NEDD8-activating enzyme.",

author = "Zhong, {Hai Jing} and Hui Yang and Chan, {Daniel Shiu Hin} and Leung, {Chung Hang} and Wang, {Hui Min} and Ma, {Dik Lung}",

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doi = "10.1371/journal.pone.0049574",

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T1 - A Metal-Based Inhibitor of NEDD8-Activating Enzyme

AU - Zhong, Hai Jing

AU - Yang, Hui

AU - Chan, Daniel Shiu Hin

AU - Leung, Chung Hang

AU - Wang, Hui Min

AU - Ma, Dik Lung

PY - 2012/11/19

Y1 - 2012/11/19

N2 - A cyclometallated rhodium(III) complex [Rh(ppy)2(dppz)]+ (1) (where ppy = 2-phenylpyridine and dppz = dipyrido[3,2-a:2′,3′-c]phenazine dipyridophenazine) has been prepared and identified as an inhibitor of NEDD8-activating enzyme (NAE). The complex inhibited NAE activity in cell-free and cell-based assays, and suppressed the CRL-regulated substrate degradation and NF-κB activation in human cancer cells with potency comparable to known NAE inhibitor MLN4924. Molecular modeling analysis suggested that the overall binding mode of 1 within the binding pocket of the APPBP1/UBA3 heterodimer resembled that for MLN4924. Complex 1 is the first metal complex reported to suppress the NEDDylation pathway via inhibition of the NEDD8-activating enzyme.

AB - A cyclometallated rhodium(III) complex [Rh(ppy)2(dppz)]+ (1) (where ppy = 2-phenylpyridine and dppz = dipyrido[3,2-a:2′,3′-c]phenazine dipyridophenazine) has been prepared and identified as an inhibitor of NEDD8-activating enzyme (NAE). The complex inhibited NAE activity in cell-free and cell-based assays, and suppressed the CRL-regulated substrate degradation and NF-κB activation in human cancer cells with potency comparable to known NAE inhibitor MLN4924. Molecular modeling analysis suggested that the overall binding mode of 1 within the binding pocket of the APPBP1/UBA3 heterodimer resembled that for MLN4924. Complex 1 is the first metal complex reported to suppress the NEDDylation pathway via inhibition of the NEDD8-activating enzyme.

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A Metal-Based Inhibitor of NEDD8-Activating Enzyme

Abstract

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