You are here

J Med Chem DOI:10.1021/acs.jmedchem.7b00395

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

Publication TypeJournal Article
Year of Publication2017
AuthorsPalomo, 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
JournalJ Med Chem
Volume60
Issue12
Pages4983-5001
Date Published2017 Jun 22
ISSN1520-4804
KeywordsAllosteric 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
Abstract

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.

DOI10.1021/acs.jmedchem.7b00395
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28548834?dopt=Abstract

Alternate JournalJ. Med. Chem.
PubMed ID28548834