2. Academic Validation
  3. Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes

Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes

  • Bioorg Med Chem Lett. 2016 Jan 15;26(2):424-428. doi: 10.1016/j.bmcl.2015.11.099.
Laura Simon-Szabó 1,  Márton Kokas 1,  Zoltán Greff 2,  Sándor Boros 2,  Péter Bánhegyi 2,  Lilián Zsákai 2,  Csaba Szántai-Kis 2,  Tibor Vantus 3,  József Mandl 3,  Gábor Bánhegyi 4,  István Vályi-Nagy 5,  László Őrfi 6,  Axel Ullrich 7,  Miklós Csala 4,  György Kéri 8
Affiliations

Affiliations

  • 1 MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
  • 2 Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
  • 3 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.
  • 4 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
  • 5 United St. Istvan and St. Laszlo Hospital, 1097 Budapest, Hungary.
  • 6 Vichem Chemie Research Ltd, 1022 Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
  • 7 Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
  • 8 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.
PMID: 26704265 DOI: 10.1016/j.bmcl.2015.11.099
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.

Keywords

IRS-1 phosphorylation; Lipotoxicity; Pyrido[2,3-d]pyrimidin; Type 2 diabetes; c-Jun N-terminal kinase.

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