title: Small Molecules Targeting Human N-Acetylmannosamine Kinase.
abstract: N-Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. In search of effective inhibitors of MNK we applied high-throughput screening of drug-like small molecules. By applying different orthogonal assays for their validation we identified four potential MNK-specific inhibitors with IC50values in the low-micromolar range. Molecular modelling of the inhibitors into the active site of MNK supports their binding to the sugar or the ATP-binding pocket of the enzyme or both. These compounds are promising for downregulation of the sialic acid content of glycoconjugates and for studying the functional contribution of sialic acids to disease development.
authors.affiliation: Beuth Hochschule für Technik Berlin, Seestrasse 64, 13347, Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Hinderlich
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité-Universitätsmedizin Berlin, Arnimalee 22, 14195, Berlin, Germany.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Wratil
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Oder
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lisurek
authors.affiliation: Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité-Universitätsmedizin Berlin, Arnimalee 22, 14195, Berlin, Germany.
authors.forename: Long D
authors.initials: LD
authors.lastname: Nguyen
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Jens P
authors.initials: JP
authors.lastname: von Kries
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125, Berlin, Germany.|Humboldt Universität zu Berlin, Department Chemie, Brook-Taylor-Strasse 2, 12489, Berlin, Germany.
authors.forename: Christian P R
authors.identifier: 0000-0001-7457-4742
authors.initials: CPR
authors.lastname: Hackenberger
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D020816:Amino Acid Motifs; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006031:Glycosylation; D057166:High-Throughput Screening Assays; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry*; D007700:Kinetics; D062105:Molecular Docking Simulation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012794:Sialic Acids / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D011994:Recombinant Proteins; D012794:Sialic Acids; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C018765:N-acylmannosamine kinase
keywords: N-acetylmannosamine kinases; high-throughput screening; inhibitors; sialic acids; small molecules