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

46 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

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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\}",

year = "2012",

month = nov,

day = "19",

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

language = "English",

volume = "7",

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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.

UR - https://www.scopus.com/pages/publications/84869784138

U2 - 10.1371/journal.pone.0049574

DO - 10.1371/journal.pone.0049574

M3 - Journal article

C2 - 23185368

AN - SCOPUS:84869784138

SN - 1932-6203

VL - 7

JO - PLoS ONE

JF - PLoS ONE

IS - 11

M1 - e49574

ER -

A Metal-Based Inhibitor of NEDD8-Activating Enzyme

Abstract

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