title: Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes.
abstract: Activation of various interacting stress kinases, particularly the c-Jun N-terminal kinases (JNK), and a concomitant phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in β-cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes.
authors.affiliation: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: Laura
authors.initials: L
authors.lastname: Simon-Szabó
authors.affiliation: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: Márton
authors.initials: M
authors.lastname: Kokas
authors.affiliation: Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Greff
authors.affiliation: Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Boros
authors.affiliation: Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Bánhegyi
authors.affiliation: Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
authors.forename: Lilián
authors.initials: L
authors.lastname: Zsákai
authors.affiliation: Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szántai-Kis
authors.affiliation: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary; Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Vantus
authors.affiliation: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary; Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Mandl
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Bánhegyi
authors.affiliation: United St. Istvan and St. Laszlo Hospital, 1097 Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Vályi-Nagy
authors.affiliation: Vichem Chemie Research Ltd, 1022 Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Őrfi
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Csala
authors.affiliation: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary; Vichem Chemie Research Ltd, 1022 Budapest, Hungary. Electronic address: keri.gyorgy@med.semmelweis-univ.hu.
authors.forename: György
authors.initials: G
authors.lastname: Kéri
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; D011743:Pyrimidines; D012694:Serine; D048031:JNK Mitogen-Activated Protein Kinases
keywords: IRS-1 phosphorylation; Lipotoxicity; Pyrido[2,3-d]pyrimidin; Type 2 diabetes; c-Jun N-terminal kinase