title: Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity.
abstract: NEK2 is a conserved mitotic regulator critical for cell cycle progression. Aberrant expression of NEK2 has been found in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. In the present study, we have identified a novel compound MBM-5, which was found to bind to NEK2 with high affinity by docking simulations study. MBM-5 potently inhibited NEK2 kinase activity in vitro in a concentration-dependent manner. MBM-5 also suppressed cellular NEK2 kinase activity, as evidenced by the decreased phosphorylation of its substrate Hec1 on S165 in a concentration- and time-dependent manner. This inhibition impeded mitotic progression by inducing chromosome segregation defects and cytokinesis failure; therefore leading to accumulation of cells with ≥4N DNA content, which finally underwent apoptosis. More importantly, MBM-5 treatment effectively suppressed the tumor growth of human gastric and colorectal cancer cells xenografts. Taken together, we demonstrated that MBM-5 effectively inhibited the kinase activity of NEK2 and showed a potential application in anti-cancer treatment regimens.
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Jianbei
authors.initials: J
authors.lastname: Xi
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Mengli
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Ma
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D000072379:NIMA-Related Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases
keywords: NEK2; apoptosis; chromosome misalignment; cytokinesis failure; mitosis