Department of Chemistry
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-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. © 2012 Zhong et al.
Source Publication Title
Public Library of Science
Zhong, Hai-Jing, Hui Yang, Daniel Shiu-Hin Chan, Chung-Hang Leung, Hui-Min Wang, and Dik-Lung Ma. "A metal-based inhibitor of NEDD8-activating enzyme." PLoS ONE 7.11 (2012).