alsterpaullone and Muscular-Atrophy--Spinal

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.

Topics: 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

The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.

Topics: Adult; Animals; Benzazepines; Cells, Cultured; Child, Preschool; Drug Discovery; Embryonic Stem Cells; Fibroblasts; Gene Expression Regulation; Gene Silencing; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Indoles; Mice; Motor Neurons; Muscular Atrophy, Spinal; Mutation; Platelet-Derived Growth Factor; Small Molecule Libraries; STAT1 Transcription Factor; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein