Details of the Drug Therapeutic Target (DTT)
General Information of Drug Therapeutic Target (DTT) (ID: TTRSMW9)
DTT Name | Glycogen synthase kinase-3 beta (GSK-3B) | ||||
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Synonyms | Serine/threonine-protein kinase GSK3B; GSK-3 beta | ||||
Gene Name | GSK3B | ||||
DTT Type |
Clinical trial target
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[1] | |||
BioChemical Class |
Kinase
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UniProt ID | |||||
TTD ID | |||||
3D Structure | |||||
EC Number |
EC 2.7.11.26
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Sequence |
MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTK
VIGNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSG EKKDEVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHR DIKPQNLLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDV WSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHP WTKVFRPRTPPEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALF NFTTQELSSNPPLATILIPPHARIQAAASTPTNATAASDANTGDRGQTNNAASASASNST |
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Function |
Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation. Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression. Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1.
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KEGG Pathway |
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Reactome Pathway |
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Molecular Interaction Atlas (MIA) of This DTT
Molecular Interaction Atlas (MIA) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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6 Clinical Trial Drug(s) Targeting This DTT
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5 Patented Agent(s) Targeting This DTT
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3 Discontinued Drug(s) Targeting This DTT
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74 Investigative Drug(s) Targeting This DTT
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Molecular Expression Atlas (MEA) of This DTT
References
1 | Evidence for irreversible inhibition of glycogen synthase kinase-3beta by tideglusib. J Biol Chem. 2012 Jan 6;287(2):893-904. | ||||
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2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | ||||
3 | 9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer. Sci Rep. 2019 Dec 27;9(1):19977. | ||||
4 | The GSK3 kinase inhibitor lithium produces unexpected hyperphosphorylation of -catenin, a GSK3 substrate, in human glioblastoma cells. Biol Open. 2018 Jan 26;7(1):bio030874. | ||||
5 | Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015).Expert Opin Ther Pat. 2017 Jun;27(6):657-666. | ||||
6 | Company report (Neurim Pharmaceuticals) | ||||
7 | Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models. Eur J Med Chem. 2009 Jun;44(6):2361-71. | ||||
8 | Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003 Mar;52(3):588-95. | ||||
9 | 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta. Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6. | ||||
10 | Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70. | ||||
11 | Identification of novel scaffold of benzothiazepinones as non-ATP competitive glycogen synthase kinase-3beta inhibitors through virtual screening. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7232-6. | ||||
12 | AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans.J Neurochem.2013 May;125(3):446-56. | ||||
13 | Discovery of potent and bioavailable GSK-3beta inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1693-6. | ||||
14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029796) | ||||
15 | Synthesis and antiproliferative activity of 7-azaindirubin-3'-oxime, a 7-aza isostere of the natural indirubin pharmacophore. J Nat Prod. 2009 Dec;72(12):2199-202. | ||||
16 | Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2. Bioorg Med Chem Lett. 2010 Mar 15;20(6):1985-9. | ||||
17 | Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for ... J Nat Prod. 2007 Sep;70(9):1397-405. | ||||
18 | Novel 8-arylated purines as inhibitors of glycogen synthase kinase. Eur J Med Chem. 2010 Aug;45(8):3389-93. | ||||
19 | Novel GSK-3beta inhibitors from sequential virtual screening. Bioorg Med Chem. 2008 Jan 15;16(2):636-43. | ||||
20 | Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47. | ||||
21 | 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9. | ||||
22 | Manzamine B and E and ircinal A related alkaloids from an Indonesian Acanthostrongylophora sponge and their activity against infectious, tropical p... J Nat Prod. 2006 Jul;69(7):1034-40. | ||||
23 | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. | ||||
24 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | ||||
25 | The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315. | ||||
26 | Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. | ||||
27 | Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74. | ||||
28 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2030). | ||||
29 | Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. J Med Chem. 2006 Apr 20;49(8):2363-6. | ||||
30 | Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors. Bioorg Med Chem Lett. 2002 Jun 3;12(11):1525-8. | ||||
31 | Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors. Bioorg Med Chem. 2004 Jun 15;12(12):3167-85. | ||||
32 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | ||||
33 | Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells. Bioorg Med Chem. 2010 Sep 15;18(18):6785-95. | ||||
34 | Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J Med Chem. 2004 Feb 12;47(4):935-46. | ||||
35 | The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg Med Chem Lett. 2009 Jul 1;19(13):3586-92. | ||||
36 | The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81. | ||||
37 | Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors. Eur J Med Chem. 2010 Feb;45(2):805-10. | ||||
38 | 2-N-Methyl modifications and SAR studies of manzamine A. Bioorg Med Chem. 2008 Jul 15;16(14):6702-6. | ||||
39 | Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2344-9. | ||||
40 | Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1353-7. | ||||
41 | Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52. | ||||
42 | First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem. 2009 Jan 22;52(2):293-307. | ||||
43 | 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 effi... J Med Chem. 2004 Sep 9;47(19):4716-30. | ||||
44 | Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nat Chem Biol. 2005 Jul;1(2):74-84. | ||||