Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors

Shen, Lan; Prouty, Catherine; Conway, Bruce R.; Westover, Lori; Xu, Jun; Look, Richard; Chen, Xin; Beavers, Mary Pat; Roberts, J. R.; Murray, William V.; Demarest, Keith T.; Kuo, Gee‐Hong

doi:10.1016/j.bmc.2003.09.047

Cited by 32 publications

(15 citation statements)

References 46 publications

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“…, 2003); azaindolylmaleimides are slightly selective over CDK2 with little or no inhibition over 62 protein kinases (Kuo et al. , 2003; Shen et al. , 2004).…”

Section: Gsk 3 Inhibitors For Type II Diabetesmentioning

confidence: 99%

Glycogen synthase kinase 3: more than a namesake

Rayasam¹,

Tulasi²,

Sodhi³

et al. 2009

British J Pharmacology

419

355

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Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, t protein and b catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.

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“…, 2003); azaindolylmaleimides are slightly selective over CDK2 with little or no inhibition over 62 protein kinases (Kuo et al. , 2003; Shen et al. , 2004).…”

Section: Gsk 3 Inhibitors For Type II Diabetesmentioning

confidence: 99%

Glycogen synthase kinase 3: more than a namesake

Rayasam¹,

Tulasi²,

Sodhi³

et al. 2009

British J Pharmacology

419

355

View full text Add to dashboard Cite

show abstract

“…5) have GSK3b inhibitors in Phase I clinical trials for AD. Small molecule inhibitors such as lithium [Gould and Manji, 2005;Aghdam and Barger, 2007], AR-A014418 [Bhat et al, 2003], the paullones [Kunick et al, 2004], indirubins [Leclerc et al, 2001], maleimide analogues [Engler et al, 2004[Engler et al, , 2005Shen et al, 2004], hymenialdisine [Meijer, 2000;Wan, 2004] 2,4-disubstituted thiadiazolidiones [Castro et al, 2008], aloisines [Mettey et al, 2003], and amino pyrazoles [Witherington, 2006] have all been reported as GSK3 inhibitors (Fig. 6), some that also inhibit CDK5.…”

Section: Cdk 5 and Gsk 3 Have Been Actively Targeted As Tau Kinasesmentioning

confidence: 98%

Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease

Savage

Gingrich²

2009

Drug Development Research

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Pharmaceutical approaches to slow the progression of Alzheimer's disease (AD) have focused primarily on reducing production or increasing clearance of amyloid b peptide (Ab Key words: Alzheimer; tau; cyclin-dependent kinase 5; CDK5; glycogen synthase kinase 3; GSK3; c-Jun N-terminal kinase; JNK; p38 kinase; Casein kinase 1; CK1; Rho kinase; Rock; p21-activating kinase; Pak AMYLOID AND TAU BRAIN PATHOLOGIES HAVE DIRECTED KINASE TARGET EFFORTSAlzheimer's disease (AD) is characterized by the accumulation in hippocampal and cortical brain regions of two insoluble, proteinaceous aggregates. The amyloid plaque is composed primarily of extraneuronal deposits of amyloid b (Ab), which is cleaved from the amyloid precursor protein (APP) by two intracellular proteases, b-and g-secretase [Selkoe, 1991;Sisodia and St George-Hyslop, 2002;Vetrivel and Thinakaran, 2006] (Fig. 1). a-Secretase cuts approximately in the middle of Ab after lysine-16, precluding its formation. The neurofibrillary tangle (NFT) is composed primarily of intraneuronal deposits of hyperphosphorylated tau protein (ptau) (Fig. 2) Iqbal and Grundke-Iqbal, 2006;Hyman et al., 2005], thought to result from an imbalance of kinase and phosphatase activity. Together, amyloid deposits and neurofibrillary tangles define the AD brain, yet, are not unique to AD [Askanas and Engel, 2007;Hutton, 2001]. How these insoluble proteins contribute to the inflammation, neuronal and synaptic loss and behavioral decline that is also characteristic of AD is unknown. These pathologies have directed drug discovery efforts to slow the progression of AD, with the goal of reducing levels of Ab and ptau. Animal model systems have been developed incorporating increased expression of APP and tau, and with these systems, upstream targets such as secretases and kinases have been studied. This review will focus on a number of protein kinase targets implicated in AD pathology and the DDR Published online in Wiley InterScience (www.interscience.wiley. com).

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“…Starting from the indolylcarbazole core of staurosporine, which is a modestly selective, pan-kinase inhibitor, much research effort has led to compounds with improved selectivity profiles including bisazaindolylmaleimide derivatives such as 4 [92] or 5 [93]. This work has also been extended to the use of analogs lacking the macrocyclic ring such as 6 [94] or 7 [95] which show excellent GSK-3β inhibitory activity both in vitro and also in whole cells (EC 50 40nM and 32nM respectively for inhibition of activation of glycogen synthase in HEK293 cells).…”

Section: Glycogen Synthase Kinase (Gsk)-3mentioning

confidence: 99%

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

Churcher

2006

CTMC

123

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The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.

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Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors

Cited by 32 publications

References 46 publications

Glycogen synthase kinase 3: more than a namesake

Glycogen synthase kinase 3: more than a namesake

Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

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