title: Discovery of a novel NEDD8 Activating Enzyme Inhibitor with Piperidin-4-amine Scaffold by Structure-Based Virtual Screening.
abstract: NEDD8 activating enzyme (NAE) plays an important role in regulating intracellular proteins with key parts in a broad array of cellular functions. Here, we report a structure-based virtual screening of a compound library containing 50 000 small molecular entities against the active site of NAE. Computational docking and scoring followed by biochemical screening and target validation lead to the identification of 1-benzyl-N-(2,4-dichlorophenethyl) piperidin-4-amine (M22) as a selective NAE inhibitor. M22 is reversible for NAE, inhibits multiple cancer cell lines with GI50 values in the low micromolar range, and induces apoptosis in A549 cells. Furthermore, it produces tumor inhibition in AGS xenografts in nude mice and low acute toxicity in a zebrafish model. M22, a novel NAE inhibitor, represents a promising lead structure for the development of new antitumor agents.
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Yuan
authors.affiliation: College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Minfang
authors.initials: M
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University , No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Ping-Kai
authors.initials: PK
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D044763:Ubiquitin-Conjugating Enzymes; C581960:UBE2F protein, human