GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Abstract

Inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. The known GSK-3 inhibitors are of diverse chemotypes and mechanisms of action and include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate-competitive inhibitors. Here we describe the variety of GSK-3 inhibitors with a specific emphasis on their biological activities in neurons and neurological disorders. We further highlight our current progress in the development of non-ATP-competitive inhibitors of GSK-3. The available data raise the hope that one or more of these drug design approaches will prove successful at stabilizing or even reversing the aberrant neuropathology and cognitive deficits of certain central nervous system disorders.

Keywords: CNS; GSK-3; GSK-3 inhibitors; protein kinases.

Figure 1

Some ATP-competitive GSK-3 inhibitors with potential for CNS disorders. (A) Isolated from marine organisms. (B) Small molecules from organic synthesis programs.

Figure 2

ATP non-competitive GSK-3 inhibitors with potential for CNS disorders. (A) Small molecules from organic synthesis programs. (B) Natural compounds isolated from marine organisms. (C) Peptide competitive with substrate.

Figure 3

GSK-3-interacting sites with ATP-competitive inhibitors, substrates, and L803-mts. (A) Sites interacting with ATP or ATP-competitive inhibitors are indicated. These interacting sites are located at the interface within the N- and C-lobes of the catalytic domain. F67 (yellow) locates the P-loop interacting with ATP (B) Distinct and overlapping element in GSK-3 interaction with substrates and inhibitors. Sites interacting with substrates: F67 (yellow), 89–95 loop (red), phosphate binding pocket (P-binding pocket, blue). D181 (orange) interacts with the pseudosubstrate. Sites interacting with L803-mts: F93 (within the 89–95 loop), hydrophobic patch (V214, I217 Y216 magenta), and the phosphate binding pocket (blue). GSK-3 structure is based on PDB code 1gng and images were processed by PyMol software.