A Metal-Based Inhibitor of NEDD8-Activating Enzyme

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-ba...

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Detalles Bibliográficos
Autores principales: Zhong, Hai-Jing, Yang, Hui, Chan, Daniel Shiu-Hin, Leung, Chung-Hang, Wang, Hui-Min, Ma, Dik-Lung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501507/
https://www.ncbi.nlm.nih.gov/pubmed/23185368
http://dx.doi.org/10.1371/journal.pone.0049574
Descripción
Sumario: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.

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