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SB-415286 is a potent and selective cell permeable inhibitor of glycogen synthase kinase-3 (GSK-3) with Ki of 31 nM. It shows similar potency against GSK-3 and GSK3β [1].

SB-415286 inhibited GSK-3 activity and promoted glycogen synthesis in human liver cells and induced expression of reporter gene regulated by catenin-LEF/TCF in HEK293 cells [1]. In primary neurons, it can prevent cell death induced by repressed PI3k pathway activity [2]. Further studies showed that reduced GSK3β activity induced by SB-415286 could inhibit down-regulation of cyclin D1, cell cycle arrest and chemosensitivity, which were all mediated by rapamycin [3]. Pharmacologic inhibition of GSK-3β dramatically impaired p53-dependent transactivation of p21 and Puma but facilitated p53-dependent conformational activation of Bax, resulting in the conversion of p53-mediated damage response from cell cycle arrest to apoptosis [4]. SB-415286 reduced ischemia-reperfusion injury by mechanisms which were associated with mitochondria. SB-415286 reduced adenine nucleotide transport and phosphorylation of VDAC, then increased Bcl-2 binding to mitochondria and blocked opening of the mitochondrial permeability transition pore in cardiomyocytes [5]. SB-415286 had protective effect of hippocampal neurons on radiation-induced apoptosis as well. GSK-3β inhibition induced by SB-415286 could result in the upregulation of MDM2, which, in turn, regulated p53 degradation and p53-dependent cellular responses [6].

Recent research in a mouse model further confirmed that SB-415286 is a neuroprotectant against radiation-induced central nervous system necrosis. Mice treated with SB415286 prior to irradiation (i.e. a single 45-Gy fraction targeted to the left hemisphere), showed significant protection from radiation-induced necrosis, which was determined by in vivo MRI, in contrast with DMSO-treated mice [7].

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