Target Validation Information
Target ID T70977
Target Name Glycogen synthase kinase-3 beta
Target Type
Clinical Trial
Drug Potency against Target N,8-diphenyl-9H-purin-6-amine Drug Info IC50 = 16 nM [530921]
3-(6-(phenylamino)-9H-purin-8-yl)benzonitrile Drug Info IC50 = 26 nM [530921]
N-(8-(3-cyanophenyl)-9H-purin-6-yl)pentanamide Drug Info IC50 = 1220 nM [530921]
AS-601245 Drug Info IC50 = 40 nM [529039]
PYRAZOLOPYRIDAZINE 2 Drug Info Ki = 10 nM [527192]
NU-6102 Drug Info IC50 = 40 nM [527906]
3-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione Drug Info IC50 = 520 nM [529153]
PYRAZOLOPYRIDAZINE 1 Drug Info Ki = 10 nM [527192]
ELLAGIC ACID Drug Info IC50 = 7500 nM [528129]
8-O-(4-chlorobenzenesulfonyl)manzamine F Drug Info IC50 = 7200 nM [528991]
N-(6-phenyl-1H-indazol-3-yl)butyramide Drug Info IC50 = 390 nM [530757]
N-(6-(pyridin-3-yl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 5900 nM [530757]
BISINDOLYLMALEIMIDE IX Drug Info IC50 = 38 nM [525872]
AR-A014418 Drug Info IC50 = 100 nM [529753]
AZAKENPAULLONE Drug Info IC50 = 18 nM [526916]
CT-98024 Drug Info IC50 = 0.56 nM [530695]
KENPAULLONE Drug Info IC50 = 23 nM [526916]
12,13-DEHYDRO-8-O-ACETYLMANZAMINE A Drug Info IC50 = 4800 nM [528991]
PAULLONE Drug Info IC50 = 100 nM [530695]
N-(6-benzyl-1H-indazol-3-yl)butyramide Drug Info IC50 = 4140 nM [530735]
N-(6-phenethyl-1H-indazol-3-yl)butyramide Drug Info IC50 = 8525 nM [530735]
N-(6-(thiophen-3-yl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 935 nM [530735]
9-N-ETHYL-8-ETHOXY-MANZAMINE A Drug Info IC50 = 10400 nM [528991]
N-(6-(4-hydroxyphenyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 44 nM [530735]
(E)-N-(6-(prop-1-enyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 2459 nM [530735]
N-(6-(3-hydroxyphenyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 94 nM [530735]
N-(6-(pyridin-4-yl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 661 nM [530735]
N-(6-(furan-3-yl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 260 nM [530735]
N-(6-(2-chlorophenyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 1353 nM [530735]
N-(6-(4-fluorophenyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 5008 nM [530735]
N-(6-(trifluoromethyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 195 nM [530735]
N-(6-bromo-1H-indazol-3-yl)butyramide Drug Info IC50 = 198 nM [530735]
RO-320432 Drug Info IC50 = 20 nM [530695]
6-hydroxymanzamine A Drug Info IC50 = 16600 nM [528991]
Thieno analogue of kenpaullone Drug Info IC50 = 120 nM [526916]
12,13-DEHYDROMANZAMINE A Drug Info IC50 = 5400 nM [528991]
N-(6-(4-aminophenyl)-1H-indazol-3-yl)butyramide Drug Info IC50 = 76 nM [530735]
N-(6-chloro-5-p-tolyl-1H-indazol-3-yl)butyramide Drug Info IC50 = 14000 nM [530735]
N-(6-chloro-1H-indazol-3-yl)butyramide Drug Info IC50 = 354 nM [530735]
LEUCETTAMINE B Drug Info IC50 = 15000 nM [530492]
Enzastaurin Drug Info IC50 = 30 nM [552971]
MANZAMINE A Drug Info IC50 = 10200 nM [529574]
TWS-119 Drug Info IC50 = 30 nM [527964]
N-(6-chloro-5-phenyl-1H-indazol-3-yl)butyramide Drug Info IC50 = 80 nM [530757]
4-(5-bromo-1H-indol-3-yl)pyrimidin-2-amine Drug Info IC50 = 2000 nM [529753]
Action against Disease Model SB216763 Pharmacological GSK-3 inhibitors such as the maleimide SB216763 or the aminopyrazole GSK inhibitor XIII inhibited AR-dependent reporter gene activity and AR expression in vitro.Analysis of androgen-induced nuclear translocation of the AR was performed in PC3 cells transfected with pAR-t1EosFP coding for EosAR, a green fluorescent AR fusion protein. When grown in presence ofandrogens, EosAR was predominantly nuclear. Incubation with SB216763 before and after androgen treatment almost completely reduced nuclear EosAR. In contrast, the thiazole-containing urea compound AR-A014418 increased rather than decreased AR-expression/function. Although not all GSK inhibitors affected AR-stability/function, our observations suggest a potential new therapeutic application for some of these compounds in prostate cancer [552822] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Here, we analyzed the ability of heterozygote GSK-3beta knockout (GSK+/-) mice to form memories. In the Morris water maze (MWM), learning and memory performance of GSK+/- mice was no different from that of wild-type (WT) mice for the first 3 days of training. With continued learning on subsequent days, however, retrograde amnesia was induced in GSK+/- mice, suggesting that GSK+/- mice might be impaired in their ability to form long-term memories. In contextual fear conditioning (CFC), context memory was normally consolidated in GSK+/- mice, but once the original memory was reactivated, they showed reduced freezing, suggesting that GSK+/- mice had impaired memory reconsolidation. Biochemical analysis showed that GSK-3beta was activated after memory reactivation in WT mice. Intraperitoneal injection of a GSK-3 inhibitor before memory reactivation impaired memory reconsolidation in WT mice. These results suggest that memory reconsolidation requires activation of GSK-3beta in the adult brain. [530921]
References
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Ref 530921Eur J Med Chem. 2010 Aug;45(8):3389-93. Epub 2010 Apr 28.Novel 8-arylated purines as inhibitors of glycogen synthase kinase.
Ref 530921Eur J Med Chem. 2010 Aug;45(8):3389-93. Epub 2010 Apr 28.Novel 8-arylated purines as inhibitors of glycogen synthase kinase.
Ref 552822Inhibition of glycogen synthase kinase-3 in androgen-responsive prostate cancer cell lines: are GSK inhibitors therapeutically useful? Neoplasia. 2008 Jun;10(6):624-34.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 527192J Med Chem. 2004 Sep 9;47(19):4716-30.N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.
Ref 527906Bioorg Med Chem Lett. 2006 Mar 1;16(5):1353-7. Epub 2005 Dec 1.Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR.
Ref 529153Bioorg Med Chem. 2008 Jan 15;16(2):636-43. Epub 2007 Oct 22.Novel GSK-3beta inhibitors from sequential virtual screening.
Ref 527192J Med Chem. 2004 Sep 9;47(19):4716-30.N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.
Ref 528129J Med Chem. 2006 Apr 20;49(8):2363-6.Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Ref 528991J Nat Prod. 2007 Sep;70(9):1397-405. Epub 2007 Aug 21.Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
Ref 530757Bioorg Med Chem Lett. 2010 Apr 1;20(7):2344-9. Epub 2010 Feb 2.Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics.
Ref 530757Bioorg Med Chem Lett. 2010 Apr 1;20(7):2344-9. Epub 2010 Feb 2.Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics.
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 529753Eur J Med Chem. 2009 Jun;44(6):2361-71. Epub 2008 Sep 16.Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models.
Ref 526916Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.
Ref 530695Bioorg Med Chem Lett. 2010 Mar 1;20(5):1693-6. Epub 2010 Jan 25.Discovery of potent and bioavailable GSK-3beta inhibitors.
Ref 526916Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.
Ref 528991J Nat Prod. 2007 Sep;70(9):1397-405. Epub 2007 Aug 21.Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
Ref 530695Bioorg Med Chem Lett. 2010 Mar 1;20(5):1693-6. Epub 2010 Jan 25.Discovery of potent and bioavailable GSK-3beta inhibitors.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 528991J Nat Prod. 2007 Sep;70(9):1397-405. Epub 2007 Aug 21.Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530695Bioorg Med Chem Lett. 2010 Mar 1;20(5):1693-6. Epub 2010 Jan 25.Discovery of potent and bioavailable GSK-3beta inhibitors.
Ref 528991J Nat Prod. 2007 Sep;70(9):1397-405. Epub 2007 Aug 21.Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
Ref 526916Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.
Ref 528991J Nat Prod. 2007 Sep;70(9):1397-405. Epub 2007 Aug 21.Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530735Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. Epub 2010 Jan 25.Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2.
Ref 530492Eur J Med Chem. 2010 Feb;45(2):805-10. Epub 2009 Oct 12.Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors.
Ref 552971Small molecule inhibitors of PKCTheta as potential antiinflammatory therapeutics. Curr Top Med Chem. 2009;9(7):640-54.
Ref 529574Bioorg Med Chem. 2008 Jul 15;16(14):6702-6. Epub 2008 Jun 5.2-N-Methyl modifications and SAR studies of manzamine A.
Ref 527964Nat Chem Biol. 2005 Jul;1(2):74-84.Diversity-oriented synthesis: exploring the intersections between chemistry and biology.
Ref 530757Bioorg Med Chem Lett. 2010 Apr 1;20(7):2344-9. Epub 2010 Feb 2.Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics.
Ref 529753Eur J Med Chem. 2009 Jun;44(6):2361-71. Epub 2008 Sep 16.Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models.

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