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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Caco-2 Cells
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Cell Line, Tumor
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Cell-Free System
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Cyclopentanes / pharmacology
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / metabolism
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Dimerization
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Dose-Response Relationship, Drug
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Humans
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Inhibitory Concentration 50
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Ligands
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Luciferases / metabolism
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Magnetic Resonance Spectroscopy / methods
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Metals / chemistry*
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Models, Chemical
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Molecular Conformation
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NEDD8 Protein
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NF-kappa B / metabolism
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Protein Binding
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Pyridines / chemistry
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Pyrimidines / pharmacology
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Rhodium / chemistry
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Ubiquitin-Activating Enzymes
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Ubiquitins / chemistry*
Substances
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Cyclopentanes
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DNA-Binding Proteins
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Ligands
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Metals
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NEDD8 Protein
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NEDD8 protein, human
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NF-kappa B
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Pyridines
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Pyrimidines
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Ubiquitins
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2-phenylpyridine
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Rhodium
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Luciferases
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Ubiquitin-Activating Enzymes
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NAE protein, human
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pevonedistat
Grants and funding
This work is supported by Hong Kong Baptist University (FRG2/11-12/009), Environment and Conservation Fund (ECF Project 3/2010), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM,HKBU), the Health and Medical Research Fund (HMRF/11101212), the Research Grants Council (HKBU/201811) and the University of Macau (SRG013-ICMS12-LCH,MYRG091(Y1-L2)-ICMS12-LCH and MYRG121 (Y1-L2)-ICMS12-LCH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.