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.

Keywords: Alzheimer’s disease; Pocketron; cancer; drug discovery; inhibitors.

Figure 1

Representation of the main GSK-3β pockets, as described in Palomo et al., 2011 [37]. The left and right panels contain the front and rear views, respectively.

Figure 2

Front view representation of GSK-3β, with the main pockets found by Pocketron having the same colors as the closest pockets in Palomo et al., 2011 [37] (left panel of Figure 1). Note that the pockets are located in the same regions, although their shapes differ.

Figure 3

Front view of GSK-3β, with the main pockets (indicated as P1, P2, P4, P5 and P7) found by Pocketron represented as spheres. The spheres are color-coded, as in Figure 2, when located in the same region as the pockets identified by Palomo et al. Otherwise, the spheres are in gray or green. Black cylinders connect the pockets involved in crosstalk, with a radius proportional to the frequency of the crosstalk.

Figure 4

Structures of the available allosteric and non-ATP-competitive GSK-3β inhibitors.