|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Palomo, V, Perez, DI, Roca, C, Anderson, C, Rodriguez-Muela, N, Perez, C, Morales-Garcia, JA, Reyes, JA, Campillo, NE, Perez-Castillo, AM, Rubin, LL, Timchenko, L, Gil, C, Martinez, A|
|Journal||J Med Chem|
|Date Published||2017 Jun 22|
|Keywords||Allosteric Site, beta Catenin, Chemistry Techniques, Synthetic, Drug Design, Drug Evaluation, Preclinical, Enzyme Inhibitors, Glycogen Synthase Kinase 3, Humans, Induced Pluripotent Stem Cells, Molecular Docking Simulation, Molecular Dynamics Simulation, Muscular Atrophy, Spinal, Myoblasts, Skeletal, Myotonic Dystrophy, Quinolines, Structure-Activity Relationship|
Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3β activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects associated with strong GSK-3β inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3β may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3β inhibition exhibits therapeutic effects.
|Alternate Journal||J. Med. Chem.|