Serotonin derivatives as a new class of non-ATP-competitive receptor tyrosine kinase inhibitors

• Published in: Bioorganic & medicinal chemistry 2010-05, Vol.18 (10), p.3387-3402
• Main Authors: Büttner, Anita, Cottin, Thomas, Xu, Jing, Tzagkaroulaki, Lito, Giannis, Athanassios
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - pharmacology; Allosteric Regulation; Carbazole; Humans; Inhibitor; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - drug effects; Receptor Protein-Tyrosine Kinases - metabolism; Receptor tyrosine kinases; Serotonin; Serotonin - analogs & derivatives; Serotonin - chemistry; Serotonin - pharmacology; Tumor Cells, Cultured
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.001

Herein we report the discovery of serotonin derivatives as a novel type of non-ATP-competitive RTK inhibitors. The discovery of new templates and their subsequent elaboration to clinically useful receptor tyrosine kinase (RTK) inhibitors continues to be an important issue. RTKs are a class of enzymes responsible for the activation of different cellular signal transduction cascades. The majority of the known small molecules RTK inhibitors are ATP-competitive and they are multiple targeted inhibitors. We describe here serotonin derivatives as a new class of multiple targeted RTK inhibitors. In contrast to most other RTK inhibitors they act via a non-ATP-competitive (allosteric) mechanism. Furthermore, they are able to inhibit the proliferation of HUVE cells, fibroblasts and two cancer cell lines.