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

Laura Simon-Szabó; Márton Kokas; Zoltán Greff; Sándor Boros; Péter Bánhegyi; Lilián Zsákai; Csaba Szántai-Kis; Tibor Vantus; József Mandl; Gábor Bánhegyi; István Vályi-Nagy; László Őrfi; Axel Ullrich; Miklós Csala; György Kéri

doi:10.1016/j.bmcl.2015.11.099

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. Epub 2015 Nov 28.

Authors

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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2 / drug therapy
Diabetes Mellitus, Type 2 / metabolism
HEK293 Cells
Humans
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / pharmacology*
Insulin Receptor Substrate Proteins / metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
Phosphorylation / drug effects*
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Serine / metabolism*

Substances

Hypoglycemic Agents
Insulin Receptor Substrate Proteins
Pyrimidines
Serine
JNK Mitogen-Activated Protein Kinases