Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue

• Published in: Scientific reports 2017-03, Vol.7 (1), p.44073, Article 44073
• Main Authors: Orfi, Z., Waczek, F., Baska, F., Szabadkai, I., Torka, R., Hartmann, J., Orfi, L., Ullrich, A.
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/31; 13/95; 14/34; 14/63; 631/45/269/1146; 631/45/275; 631/92/507; 631/92/609; 631/92/613; 82/1; 9/74; Aniline Compounds - pharmacology; Animals; Antidiabetics; Beta cells; Calcium channels; Calcium influx; Cell Line; Diabetes mellitus; Glyburide - pharmacology; Humanities and Social Sciences; Hypoglycemic Agents - pharmacology; Insulin; Insulin - secretion; Insulin-Secreting Cells - secretion; Islets of Langerhans - secretion; Mode of action; Molecular Docking Simulation; multidisciplinary; Nitriles - pharmacology; Pancreas; Phosphorylation; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Quinolines - chemistry; Quinolines - pharmacology; Rats; Rodents; Science; Secretion; Signal Transduction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep44073

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.