A Metal-Based Inhibitor of NEDD8-Activating Enzyme |
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| Authors: | Hai-Jing Zhong Hui Yang Daniel Shiu-Hin Chan Chung-Hang Leung Hui-Min Wang Dik-Lung Ma |
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| Institution: | 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.; Medical School of Hannover, United States of America, |
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| Abstract: | A cyclometallated rhodium(III) complex Rh(ppy)2(dppz)]+ (1) (where ppy = 2-phenylpyridine and dppz = dipyrido3,2-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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