Glycogen Synthase Kinase Inhibitors

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Biologics 32.1: Glycogen Synthase Kinase-3	GSK-3 Signaling Interactive Pathway

Glycogen Synthase Kinase-3b (GSK-3b), a highly conserved, ubiquitously expressed serine/threonine protein kinase, is involved in the signal transduction cascades of multiple cellular processes. It is negatively regulated by protein kinase B/Akt and by the Wnt signaling pathway. Higher levels of GSK-3b have been shown in pre-tangle and in phosphorylated tau-bearing neurons. Overexpression of GSK-3b is a characteristic feature of Alzheimer's disease. GSK-3b accounts for most major phosphorylation sites of fetal and paired helical filament-tau. b-Amyloid peptides are shown to activate GSK-3b, suggesting that activation of GSK-3b is a key mechanism in pathogenesis of Alzheimer's disease. The development of GSK-3 inhibitors holds considerable promise for reducing tau phosphorylation and debilitating effects of Alzheimer's disease.

InhibitorSelect™ 96-Well Protein Kinase Inhibitor Library II (Cat. No. 539745)
Consists of 80, well-characterized, cell permeable, potent and reversible protein kinase inhibitors; the majority of which are ATP-competitive. They are supplied in a convenient 96-well plate format at a concentration of 10 mM in DMSO.

InhibitorSelect™ 384-Well Protein Kinase Inhibitor Library I (Cat. No. 539743)
Consists of 160 well-characterized, cell-permeable, potent, and reversible protein kinase inhibitors; the majority of which are ATP-competitive. They are supplied in a convenient 384-well plate format at a concentration of 10 mM in DMSO.

Aloisine, RP106 (Cat. No. 128135)
A cell-permeable, potent, selective ATP-competitive inhibitor of Cdk1/cyclin B (IC₅₀ = 700 nM), Cdk5/p25 (IC₅₀ = 1.5 mM), and GSK-3 (IC₅₀ = 920 nM).

Aloisine A (Cat. No. 128125)
Acts as a potent, selective, reversible, and ATP-competitive inhibitor of cyclin-dependent kinases (Cdks; IC₅₀ = 150 nM, 120 nM, 400 nM, and 200 nM for Cdk1/cyclin B, Cdk2/cyclin A, Cdk2/cyclin E, and Cdk5/p25, respectively), glycogen synthase kinase-3 (GSK-3; IC₅₀ = 500 nM and 1.5 µM for GSK-3a, GSK-3b, respectively), and c-Jun N-terminal kinase (JNK; IC₅₀ ~ 3 - 10 µM).

Alsterpaullone (Cat. No. 126870)
A potent inhibitor of Cdk1/cyclin B (IC₅₀ = 35 nM). Displays remarkable in vitro antitumor activity. Inhibits Tau phosphorylation at sites that are typically phosphorylated by GSK-3b in Alzheimer’s disease. Also inhibits Cdk5/p25-dependent phosphorylation of DARPP-32.

Cdk1/5 Inhibitor (Cat. No. 217720)
A 3-amino substituted pyrazoloquinoxaline compound that acts as a selective inhibitor of cyclin-dependent kinases 1 and 5 (Cdks; IC₅₀ = 0.6 µM and 0.4 µM for Cdk1/cyclin B and Cdk5/p25, respectively). Also shown to inhibit GSK-3b with (IC₅₀ = 1 µM).

Cdc7/Cdk9 Inhibitor (Cat. No. 217707)
A cell-permeable pyrrolopyridinone compound that acts as a potent, reversible, and ATP-competitive inhibitor of Cdc7 and Cdk9 (IC₅₀ = 10 and 34 nM, respectively) with good selectivity over a panel of 31 other kinases, including GSK-3b, Cdk2, Cdk1, Cdk5, MK-2, Plk1, and Chk2 (IC₅₀ = 0.22, 0.24, 0.25, 0.46, 0.47, 0.98, and 1.1 µM, respectively).

FRATtide (Cat. No. 344265)
A peptide corresponding to amino acids 188 - 226 of FRAT1 (frequently rearranged in advanced T-cell lymphomas 1), a mammalian homolog of GSK-3 binding protein. Binds to the C-terminal lobe of GSK-3 and prevents the binding of “unprimed” substrates such as axin, b-catenin and tau. Exhibits little effect on GSK-3 catalyzed phosphorylation of “primed” (pre-phosphorylated) substrates such as glycogen synthase and eIF2B.

GSK-3 Inhibitor IX in Solution (Cat. No. 361552)
Supplied as a 10 mM (500 mg/140 ml) solution of GSK-3 Inhibitor IX (Cat. No. 361550) in DMSO.

GSK-3 Inhibitor X (Cat No. 361551)
An acetoxime analog of BIO, GSK-3 Inhibitor IX (Cat. No. 361550) that exhibits greater selectivity for GSK-3a/b (IC₅₀ = 0.01 mM) over CDK5/p25, CDK2/A and CDK1/B (IC₅₀ = 2.4 mM, 4.3 mM and 63 mM, respectively).

GSK-3 Inhibitor XIII (Cat. No. 361555)
An aminopyrazole compound that acts as a potent and ATP-binding site inhibitor of GSK-3 with a K_i of 24 nM.

GSK-3 Inhibitor XIV, Control, MeBIO (Cat. No. 361556)
A cell-permeable N-methylated analog of GSK-3 Inhibitor IX, BIO (Cat. No. 361550) that serves as a relevant kinase inactive control (IC₅₀ > 92 mM for Cdk1/B, and > 100 mM for Cdk5/p25 and GSK-3a/b).

GSK-3 Inhibitor XV (Cat. No. 361558)
A cell-permeable pyridocarbazolo-cyclopentadienyl Ruthenium complex that acts as a potent, reversible and ATP-competitive inhibitor of GSK-3 (IC₅₀ = 0.7 nM and 1.1 nM for GSK-3a and GSK-3b, respectively) with moderate selectivity over PIM-1 kinase (IC₅₀ = 6 nM). Its (R)-enantiomer (IC₅₀ = 350 pM, 550 PM and 35 nM for GSK-3a, GSK-3b and PIM-1 kinase, respectively) is shown to increase the levels of b-Catenin and activate Wnt pathway in HEK293OT and 1205Lu melanoma cells at 25 nM, and induce a phenotype change in Zebrafish embryo at 1 mM.

GSK-3b Inhibitor I (Cat. No. 361540)
A thiadiazolidinone (TDZD) analog that acts as a highly selective, non-ATP competitive inhibitor of GSK-3b (IC₅₀ = 2 mM). Proposed to bind to the active site of GSK-3b.K; IC₅₀ ~ 3 - 10 µM).

GSK-3b Inhibitor II (Cat. No. 361541)
A 2-thio-[1,3,4]-oxadiazole-pyridyl derivative that acts as a potent inhibitor of GSK-3b (IC₅₀ = 390 nM).

GSK-3b Inhibitor III (Cat. No. 361542)
An oxothiadiazolidine-3-thione analog that acts as a non-ATP competitive inhibitor of GSK-3b (IC₅₀ = 10 mM).

GSK-3b Inhibitor VI (Cat. No. 361547)
A thienyl a-chloromethyl ketone compound that acts as a cell-permeable, irreversible, and non-ATP competitive inhibitor of GSK-3b (IC₅₀ = 1 mM). This reactive alkylating agent is selective towards GSK-3b and does not affect PKA activity even at concentrations as high as 100 mM.

GSK-3b Inhibitor VII (Cat. No. 361548)
A cell-permeable, selective, irreversible, and non-ATP competitive inhibitor of GSK-3b (IC₅₀ = 500 nM).

GSK-3b Inhibitor VIII (Cat. No. 361549)
A cell-permeable, potent, and highly specific inhibitor of glycogen synthase kinase-3b (GSK-3b) (IC₅₀ = 104 nM). Inhibition is competitive with respect to ATP (K_i = 38 nM).

InSolution™ GSK-3b Inhibitor VIII (Cat. No. 361557)
A 25 mM (5 mg/649 µl) solution of GSK-3b Inhibitor VIII (Cat. No. 361549) in DMSO.

GSK-3b Inhibitor IX (Cat. No. 361550)
A cell-permeable, highly potent, selective, reversible, and ATP-competitive inhibitor of GSK-3a/b (IC₅₀ = 5 nM). At higher concentrations, inhibits Cdk2/cyclin A (IC₅₀ = 300 nM) and Cdk5/p25 (IC₅₀ = 83 nM).

InSolution™ GSK-3b Inhibitor IX (Cat. No. 361552)
A 10 mM (500 µg/140 µl) solution of GSK-3 Inhibitor IX (Cat. No. 361550) in DMSO.

GSK-3b Inhibitor XI (Cat No. 361553)
A cell-permeable azaindolylmaleimide compound that acts as a potent, specific, and ATP-competitive inhibitor of GSK-3b (K_i = 25 nM) and minimally inhibits a panel of 79 commonly studied protein kinases, including several PKC isozymes.

GSK-3b Inhibitor XII, TWS119 (Cat. No. 361554)
A cell-permeable pyrrolopyrimidine compound that acts as a potent and selective inhibitor of GSK-3b (IC₅₀ = 30 nM).

GSK-3b Peptide Inhibitor (Cat. No. 361545)
A phosphorylated peptide that acts as a substrate-specific, competitive inhibitor of GSK-3b (IC₅₀ = 150 mM). At 200 mM, weakly inhibits the activities of Cdc2, CK-2, MAPK, PKA, PKB, and PKCd.

GSK-3b Peptide Inhibitor, Cell-Permeable (Cat. No. 361546)
A cell-permeable, myristoylated form of GSK-3b Peptide Inhibitor (Cat. No. 361545) with a glycine spacer. Acts as a selective, substrate-specific, competitive inhibitor of GSK-3b (IC₅₀ = 40 mM). Does not affect the activities of Cdc2, PKB, or PKC.

Indirubin-3'-monoxime (Cat. No. 402085)
A potent cell-permeable inhibitor of GSK-3b (IC₅₀ = 190 nM) and cyclin-dependent kinases (IC₅₀ = 180 nM for Cdk1).

Indirubin-3'-monoxime, 5-Iodo- (Cat. No. 402086)
A highly potent, cell-permeable inhibitor of GSK-3b (IC₅₀ = 9 nM). Reported to inhibit GSK-3b phosphorylation of human tau protein in vitro (IC₅₀ ~100 nM) and in cells (effective concentration = 20 mM). Also inhibits Cdk1 (IC₅₀ = 25 nM) and Cdk5 (IC₅₀ = 20 nM).

Indirubin-3'-monoxime-5-sulfonic Acid (Cat. No. 402088)
A highly potent, selective, ATP competitive inhibitor of Cdks 1 and 5 (IC₅₀ = 5 nM for Cdk1; IC₅₀ = 7 nM for Cdk5). Also acts as a potent inhibitor of GSK-3b (IC₅₀ = 80 nM).

Kenpaullone (Cat. No. 422000)
A potent, cell-permeable, ATP competitive inhibitor of GSK-3b (IC₅₀ = 230 nM), Lck (IC₅₀ = 470 nM) and Cdks. Inhibits Cdk1/cyclin B (IC₅₀ = 400 nM), CdK2/cyclin A (IC₅₀ = 680 nM), Cdk2/cyclin E (IC₅₀ = 7.5 mM), and Cdk5/p25 (IC₅₀ = 850 nM).