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.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhong
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Daniel Shiu-Hin
authors.initials: DS
authors.lastname: Chan
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Wang
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
mesh_terms: D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002474:Cell-Free System; D003517:Cyclopentanes / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008670:Metals / Q000737:chemistry*; D008956:Models, Chemical; D008968:Molecular Conformation; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000494:pharmacology; D012238:Rhodium / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D044764:Ubiquitin-Activating Enzymes; D014452:Ubiquitins / Q000737:chemistry*
chemical_list: D003517:Cyclopentanes; D004268:DNA-Binding Proteins; D008024:Ligands; D008670:Metals; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D011725:Pyridines; D011743:Pyrimidines; D014452:Ubiquitins; C058324:2-phenylpyridine; D012238:Rhodium; D008156:Luciferases; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat