Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases

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.