title: Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors.
abstract: REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase required for normal development and maintenance of neurons of the central and peripheral nervous systems. Deregulation of RET and hyperactivity of the RET kinase is intimately connected to several types of human cancers, most notably thyroid cancers, making it an attractive therapeutic target for small-molecule kinase inhibitors. Novel approaches, allowing external control of the activity of RET, would be key additions to the signal transduction toolbox. In this work, photoswitchable RET kinase inhibitors based on azo-functionalized pyrazolopyrimidines were developed, enabling photonic control of RET activity. The most promising compound displays excellent switching properties and stability with good inhibitory effect towards RET in cell-free as well as live-cell assays and a significant difference in inhibitory activity between its two photoisomeric forms. As the first reported photoswitchable small-molecule kinase inhibitor, we consider the herein presented effector to be a significant step forward in the development of tools for kinase signal transduction studies with spatiotemporal control over inhibitor concentration in situ.
authors.affiliation: Department of Chemistry and Chemical Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.
authors.forename: Rubén
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: Department of Chemistry and Chemical Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.
authors.forename: Jesper R
authors.initials: JR
authors.lastname: Nilsson
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Göteborg, Sweden.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solano
authors.affiliation: Department of Chemistry and Chemical Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Andréasson
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Göteborg, Sweden.
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
mesh_terms: D001665:Binding Sites; D003692:Delayed-Action Preparations / Q000138:chemical synthesis*; D015195:Drug Design; D008027:Light; D010777:Photochemistry / Q000379:methods*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000528:radiation effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D003692:Delayed-Action Preparations; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases