A Metal-Based Inhibitor of NEDD8-Activating Enzyme

Hai-Jing Zhong,Chung-Hang Leung,Hui Yang,Daniel Shiu-Hin Chan,Dik-Lung Ma,Hui-Min Wang,Roland Seifert

doi:10.1371/journal.pone.0049574

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.

Highlights

The serendipitous discovery of the chemotherapeutic properties of the well-known anticancer drug cisplatin has aroused considerable interest in the area of medicinal inorganic chemistry [1,2,3,4,5,6,7,8]
The impact of 1 on the NEDD8-activating enzyme (NAE) activity was first evaluated by a cell-free assay that measures the formation of the Ubc12NEDD8 conjugation product
Recombinant human NAE was incubated with Ubc12 and NEDD8 in the presence of vehicle (DMSO) or 1

Summary

Introduction

The serendipitous discovery of the chemotherapeutic properties of the well-known anticancer drug cisplatin has aroused considerable interest in the area of medicinal inorganic chemistry [1,2,3,4,5,6,7,8]. Notable examples of cytotoxic rhodium complexes include the dirhodium(II,II) paddlewheel derivatives [12,18,19,20] that possess potent in vitro activities on a number of cancer cell lines. These complexes display strikingly different coordinative modes to double-helical DNA compared to cisplatin [21,22], and they have been reported to interact with proteins [16,23], presumably through covalent adduct formation with histidine [23,24] or cysteine residues [23,25]. Recent research has demonstrated mononuclear rhodium(III) complexes can be utilized as a molecular scaffold for the construction of structurally complex metal-based enzyme inhibitors that offer comparable potency to organic small molecules [17]

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Results

Conclusion