GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Abstract

Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.

Targeting Abnormal Tau Phosphorylation for Alzheimer’s Therapeutics

“…Mouse entorhinal cortex and hippocampus preclinical studies have indicated that tideglusib can reduce a range of disease outcomes including tau phosphorylation, Aβ deposition, neuron loss, and gliosis, and reverse spatial memory impairment in transgenic mice. Furthermore, tideglusib's neuroprotective, anti-inflam-matory, and neurogenesis-inducing effects have also been validated in animal models [58]. In a phase 2 clinical trial with mild to moderate AD patients, tideglusib demonstrated an acceptable safety profile for a short-term (26 weeks) treatment, with the exception of a transient increase in serum transaminase levels and diarrhea (14-18 % in active, 11 % placebo).…”

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

“…Specific inhibition of GSK signaling attenuates APP cleavage by BACE1, ameliorating memory deficits in animal models [ 18 , 19 , 20 ]. GSK-3β is a key regulator of processes that underlie the development of Alzheimer’s disease; therefore, the search for its inhibitors has been widely studied [ 21 , 22 , 23 , 24 , 25 , 26 ]. These efforts led to the discovery of various selective and potent inhibitors, among which several exhibited activity in animal models of AD [ 27 ]; however, only one has reached clinical trials in humans to date.…”