Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

Abstract

Glycogen synthase kinase-3 (GSK-3) is associated with various key biological processes, including glucose regulation, apoptosis, protein synthesis, cell signaling, cellular transport, gene transcription, proliferation, and intracellular communication. Accordingly, GSK-3 has been implicated in a wide variety of diseases and specifically targeted for both therapeutic and imaging applications by a large number of academic laboratories and pharmaceutical companies. Here, we review the structure, function, expression levels, and ligand-binding properties of GSK-3 and its connection to various diseases. A selected list of highly potent GSK-3 inhibitors, with IC50 <20 nM for adenosine triphosphate (ATP)-competitive inhibitors and IC50 <5 μM for non-ATP-competitive inhibitors, were analyzed for structure activity relationships. Furthermore, ubiquitous expression of GSK-3 and its possible impact on therapy and imaging are also highlighted. Finally, a rational perspective and possible route to selective and effective GSK-3 inhibitors is discussed.

Radiosynthesis and in Vivo Evaluation of [11C]A1070722, a High Affinity GSK-3 PET Tracer in Primate Brain

“…15–18 Small molecule inhibitors of GSK-3 are currently under development for a broad range of central nervous system (CNS) disorders including bipolar disorder, depression, diabetes, schizophrenia, and Alzheimer’s disease. 19–22 Biological imaging of GSK-3 expression with radiolabeled small molecule inhibitors may offer a direct and more sensitive approach to monitor the clinical potential of targeted therapeutics and treatments. Noninvasive and in vivo detection of the changes in GSK-3 expression using PET can impact the choice of therapy as well as monitor the progress of treatment.…”

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

“…[1] GSK-3 plays a significant role in several pathologies including Alzheimer’s disease (AD), mood disorders, type-II diabetes, and in some cancers. [2] Specifically for neurodegenerative diseases, molecular imaging of GSK-3 can indicate target engagement by GSK-3 therapeutics and offer a path to diagnostic agents that not only correlates with early cognitive impairment, but also increased tau hyperphosphorylation, [2a, 3] increased amyloid-production [4] and local plaque-associated glial-mediated inflammatory responses; all of which are hallmarks of AD and non-AD tauopathies. GSK-3 plays a key role in AD evident from: (i) the abundance and dysregulation of GSK-3 in the AD brain, [5] (ii) reduced tau phosphorylation (pTau) induced by treatment with GSK-3β inhibitors [6] and, (iii) genetic studies suggesting GSK-3 is fundamental in the pathogenesis of sporadic and familial AD.…”

PAR ‐3 controls endothelial planar polarity and vascular inflammation under laminar flow

“…Additionally, long-term treatment with fasudil improves vascular inflammation, remodeling, and atherosclerosis [54]. GSK3b is also involved in a wide variety of disease states including inflammation, but to generate a kinase activity-specific inhibitor is challenging [57]. GSK3b is also involved in a wide variety of disease states including inflammation, but to generate a kinase activity-specific inhibitor is challenging [57].…”