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a metal-based inhibitor of nedd8-activating enzyme一个金属nedd8-activating酶的抑制剂
A Metal-Based Inhibitor of NEDD8-Activating Enzyme
1. 2. 2 1 3
Hai-Jing Zhong , Hui Yang , Daniel Shiu-Hin Chan , Chung-Hang Leung , Hui-Min Wang , Dik-
Lung Ma2*
1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China, 2 Department of Chemistry,
Hong Kong Baptist University, Kowloon Tong, Hong Kong, China, 3 Department of Fragrance and Cosmetic Science, Center of Excellence for Environmental Medicine,
Kaohsiung Medical University, Kaohsiung, Taiwan
Abstract
A cyclometallated rhodium(III) complex [Rh(ppy) (dppz)]+ (1) (where ppy = 2-phenylpyridine and dppz = dipyrido[3,2-a:29,3 9-
2
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-kB 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.
Citation: Zhong H-J, Yang H, Chan DS-H, Leung C-H, Wang H-M, et al. (2012) A Metal-Based Inhibitor of NEDD8-Activating Enzyme. PLoS ONE 7(11): e49574.
doi:10.1371/journal.pone.0049574
Editor: Roland Seifert, Medical School of Hannover, United States of America
Received September 17, 2012; Accepted Oct
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