Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects
| Autor: | Sivaraman Dandapani, Jen Q. Pan, Andrew R. Germain, Shannon Nguyen, Michel Weïwer, Deepika Walpita, Michelle Palmer, Joshua R. Sacher, Linda Ross, José Carlos Rodríguez Pérez, Michael C. Lewis, Partha P. Nag, Michelle Walk, David E. Olson, Debasis Patnaik, Anne-Laure Barbe, Jaime H. Cheah, Shailesh Metkar, Benito Munoz, Yan-Ling Zhang, Kimberly Stegmaier, Arthur J. Campbell, Stuart L. Schreiber, W. Frank An, Edward M. Scolnick, Florence F. Wagner, Joshua Ketterman, Stephen J. Haggarty, Edward B. Holson, Fanny Lazzaro, Xi Shi, David Fei, Doug Barker, Taner Kaya, Joshua A. Bishop, Jennifer P. Gale |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
animal structures Kinase medicine.drug_class Wnt signaling pathway Mood stabilizer macromolecular substances General Medicine Biology Biochemistry Serine 03 medical and health sciences Glycogen Synthase Kinase 3 030104 developmental biology In vivo GSK-3 Drug Design medicine Molecular Medicine Phosphorylation Animals Humans Kinome Protein Kinase Inhibitors |
| Zdroj: | ACS chemical biology. 11(7) |
| ISSN: | 1554-8937 |
| Popis: | The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in in vitro systems or in vivo models. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders. |
| Databáze: | OpenAIRE |
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