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

作者：Palomo Valle; Perez Daniel I; Roca Carlos; Anderson Cara; Rodriguez Muela Natalia; Perez Concepcion; Morales Garcia Jose A; Reyes Julio A; Campillo Nuria E; Perez Castillo Ana M; Rubin Lee L; Timchenko Lubov; Gil Carmen; Martinez Ana

来源：Journal of Medicinal Chemistry, 2017, 60(12): 4983-5001.

DOI：10.1021/acs.jmedchem.7b00395

Glycogen synthase kinase 3 beta (GSK-3 beta) is a central target in several unmet diseases. To increase the specificity of GSK-3 beta inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3 beta activity. Design synthesis, structure activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3 beta are presented here. Furthermore, we show how allosteric binders may overcome the beta-catenin side effects associated with strong GSK-3 beta 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 it 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-3 beta may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3 beta inhibition exhibits therapeutic effects.

• 出版日期2017-6-22