GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

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.Hagit Eldar-Finkelman acknowledges support from FP7 EU grant #223276 “NeuroGSK3” and the Israeli Academy of Sciences. Grant# 341/10. Ana Martinez acknowledge financial support from Spanish government through Ministry of Science and Innovation MICINN (Project SAF2009-13015-C02-01) and Instituto de Salud Carlos III ISCiii project no. RD07/0060/0015 (RETICS program).Peer reviewedPeer Reviewe