title: Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue.
abstract: According to clinical data, some tyrosine kinase inhibitors (TKIs) possess antidiabetic effects. Several proposed mechanisms were assigned to them, however their mode of action is not clear. Our hypothesis was that they directly stimulate insulin release in beta cells. In our screening approach we demonstrated that some commercially available TKIs and many novel synthesized analogues were able to induce insulin secretion in RIN-5AH beta cells. Our aim was to find efficient, more selective and less toxic compounds. Out of several hits, we chose members from a compound family with quinoline core structure for further investigation. Here we present the studies done with these novel compounds and reveal structure activity relationships and mechanism of action. One of the most potent compounds (compound 9) lost its affinity to kinases, but efficiently increased calcium influx. In the presence of calcium channel inhibitors, the insulinotropic effect was attenuated or completely abrogated. While the quinoline TKI, bosutinib substantially inhibited tyrosine phosphorylation, compound 9 had no such effect. Molecular docking studies further supported our data. We confirmed that some TKIs possess antidiabetic effects, moreover, we present a novel compound family developed from the TKI, bosutinib and optimized for the modulation of insulin secretion.
authors.affiliation: Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Orfi
authors.affiliation: Vichem Chemie Research Ltd., Budapest, Hungary.
authors.forename: F
authors.initials: F
authors.lastname: Waczek
authors.affiliation: Vichem Chemie Research Ltd., Budapest, Hungary.
authors.forename: F
authors.initials: F
authors.lastname: Baska
authors.affiliation: Vichem Chemie Research Ltd., Budapest, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Szabadkai
authors.affiliation: Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Torka
authors.affiliation: Institute of Neuroscience, Technische Universität München, Biedersteiner Str. 29, 80802, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hartmann
authors.affiliation: Vichem Chemie Research Ltd., Budapest, Hungary.|Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Orfi
authors.affiliation: Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction
chemical_list: D000814:Aniline Compounds; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib; C037219:quinoline; D011505:Protein-Tyrosine Kinases; D005905:Glyburide