title: Development of paramagnetic probes for molecular recognition studies in protein kinases.
abstract: We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA
authors.forename: Jesus
authors.initials: J
authors.lastname: Vazquez
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chen
authors.forename: Megan
authors.initials: M
authors.lastname: Riel-Mehan
authors.forename: Aras
authors.initials: A
authors.lastname: Emdadi
authors.forename: Jason
authors.initials: J
authors.lastname: Cellitti
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Michele F
authors.initials: MF
authors.lastname: Rega
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D001665:Binding Sites; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D013113:Spin Labels / Q000138:chemical synthesis*
chemical_list: D003497:Cyclic N-Oxides; D007191:Indazoles; D009842:Oligopeptides; D013113:Spin Labels; D048031:JNK Mitogen-Activated Protein Kinases