A metal-based inhibitor of NEDD8-activating enzyme

PLoS One. 2012;7(11):e49574. doi: 10.1371/journal.pone.0049574. Epub 2012 Nov 19.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell-Free System
  • Cyclopentanes / pharmacology
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Dose-Response Relationship, Drug
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Luciferases / metabolism
  • Magnetic Resonance Spectroscopy / methods
  • Metals / chemistry*
  • Models, Chemical
  • Molecular Conformation
  • NEDD8 Protein
  • NF-kappa B / metabolism
  • Protein Binding
  • Pyridines / chemistry
  • Pyrimidines / pharmacology
  • Rhodium / chemistry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Ubiquitin-Activating Enzymes
  • Ubiquitins / chemistry*

Substances

  • Cyclopentanes
  • DNA-Binding Proteins
  • Ligands
  • Metals
  • NEDD8 Protein
  • NEDD8 protein, human
  • NF-kappa B
  • Pyridines
  • Pyrimidines
  • Ubiquitins
  • 2-phenylpyridine
  • Rhodium
  • Luciferases
  • Ubiquitin-Activating Enzymes
  • NAE protein, human
  • 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.