Glycogen Synthase Kinase (GSK) Inhibitors
Glycogen synthase kinase-3 (GSK-3), a multifunctional serine/ threonine kinase, is a key regulator of numerous signaling pathways. Two isoforms of GSK-3 are reported in mammals: a 51 kDα GSK-3α and a 47 kDa GSK-3β. GSK-3β is constitutively active in resting cells and treatment of cells with an agent, such as insulin, is shown to cause GSK-3 inactivation through a PI 3-kinase (PI 3-K)-dependent mechanism. PI 3-K-induced activation of PKB/Akt results in phosphorylation of Ser21 on GSK-3α and Ser9 on GSK-3β, which inhibits GSK-3 activity. The phosphorylated N-terminus becomes a primed pseudosubstrate that occupies the positive binding pocket and the active site of the enzyme and acts as a competitive inhibitor for true substrates. This prevents phosphorylation of substrates. Arg96 is shown to be a crucial component of the positive pocket that binds primed substrates. Small molecule inhibitors that fit in the positively charged pocket of the kinase domain of GSK-3β are useful for selectively inhibiting primed substrates. Several known GSK-3 substrates participate in a wide spectrum of cellular processes, including glycogen metabolism, transcription, translation, cytoskeletal regulation, intracellular vesicular transport, cell cycle progression, and apoptosis. Phosphorylation of these substrates by GSK-3b usually has an inhibitory effect.
Abnormalities in pathways that use GSK-3 as a regulator have been linked to several disease conditions. Hence, GSK-3 has emerged as a potential therapeutic target, particularly in noninsulin- dependent diabetes mellitus, Alzheimer’s disease, developmental disorders, and cancer. Several new GSK-3 inhibitors have recently been developed, most of which act in an ATP competitive manner. Inhibitors belonging to aloisines, the paullones, and the maleimide families, have shown promise as therapeutic agents. Due to its involvement in multiple pathways, selectivity of GSK-3 inhibition is an important factor in the development of inhibitors for therapeutic applications.
