General Information of Drug Therapeutic Target (DTT) (ID: TTRSMW9)

DTT Name Glycogen synthase kinase-3 beta (GSK-3B)
Synonyms Serine/threonine-protein kinase GSK3B; GSK-3 beta
Gene Name GSK3B
DTT Type
Clinical trial target
[1]
BioChemical Class
Kinase
UniProt ID
GSK3B_HUMAN
TTD ID
T70977
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
EC 2.7.11.26
Sequence
MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTK
VIGNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSG
EKKDEVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHR
DIKPQNLLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDV
WSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHP
WTKVFRPRTPPEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALF
NFTTQELSSNPPLATILIPPHARIQAAASTPTNATAASDANTGDRGQTNNAASASASNST
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.
KEGG Pathway
ErbB signaling pathway (hsa04012 )
Chemokine signaling pathway (hsa04062 )
Cell cycle (hsa04110 )
PI3K-Akt signaling pathway (hsa04151 )
Wnt signaling pathway (hsa04310 )
Hedgehog signaling pathway (hsa04340 )
Axon guidance (hsa04360 )
Hippo signaling pathway (hsa04390 )
Focal adhesion (hsa04510 )
Signaling pathways regulating pluripotency of stem cells (hsa04550 )
T cell receptor signaling pathway (hsa04660 )
B cell receptor signaling pathway (hsa04662 )
Neurotrophin signaling pathway (hsa04722 )
Dopaminergic synapse (hsa04728 )
Insulin signaling pathway (hsa04910 )
Melanogenesis (hsa04916 )
Prolactin signaling pathway (hsa04917 )
Thyroid hormone signaling pathway (hsa04919 )
Non-alcoholic fatty liver disease (NAFLD) (hsa04932 )
Alzheimer's disease (hsa05010 )
Hepatitis C (hsa05160 )
Measles (hsa05162 )
Influenza A (hsa05164 )
HTLV-I infection (hsa05166 )
Epstein-Barr virus infection (hsa05169 )
Pathways in cancer (hsa05200 )
Colorectal cancer (hsa05210 )
Endometrial cancer (hsa05213 )
Prostate cancer (hsa05215 )
Basal cell carcinoma (hsa05217 )
Reactome Pathway
AKT phosphorylates targets in the cytosol (R-HSA-198323 )
Regulation of HSF1-mediated heat shock response (R-HSA-3371453 )
CRMPs in Sema3A signaling (R-HSA-399956 )
Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262 )
S33 mutants of beta-catenin aren't phosphorylated (R-HSA-5358747 )
S37 mutants of beta-catenin aren't phosphorylated (R-HSA-5358749 )
S45 mutants of beta-catenin aren't phosphorylated (R-HSA-5358751 )
T41 mutants of beta-catenin aren't phosphorylated (R-HSA-5358752 )
Degradation of GLI2 by the proteasome (R-HSA-5610783 )
Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400 )
Degradation of beta-catenin by the destruction complex (R-HSA-195253 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
6 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
AMO-02 DMJRU3A Myotonic dystrophy 8C71.0 Phase 2/3 [2]
9-ING-41 DM57TY3 Myelofibrosis 2A20.2 Phase 2 [3]
Lithium DMZ3OU6 Bipolar disorder 6A60 Phase 2 [4]
LY2090314 DMTBFE4 Acute myeloid leukaemia 2A60 Phase 2 [5]
Tideglusib DME4LA1 Alzheimer disease 8A20 Phase 2 [1]
Neu-120 DMXKOUC Parkinson disease 8A00.0 Phase 1/2 [6]
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⏷ Show the Full List of 6 Clinical Trial Drug(s)
5 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
AR-A014418 DMUPN01 Ovarian cancer 2C73 Patented [7]
CHIR-99021 DMB8MNU Allergic inflammation 4A80-4A85 Patented [8]
KENPAULLONE DMAGVXW Discovery agent N.A. Patented [9]
PMID26161698-Compound-18 DM6JVR5 N. A. N. A. Patented [10]
TDZD-8 DMG6Q45 Malignant glioma 2A00.0 Patented [11]
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3 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
AZD-1080 DMIM9N1 Alzheimer disease 8A20 Discontinued in Phase 1 [12]
RO-320432 DMFZ1YW N. A. N. A. Terminated [13]
SAN-61 DMGUA9Y Alzheimer disease 8A20 Terminated [14]
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74 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
(2'Z,3'E)-7-Azaindirubin-3'-oxime DMUIOAP Discovery agent N.A. Investigative [15]
(E)-N-(6-(prop-1-enyl)-1H-indazol-3-yl)butyramide DMHKXPM Discovery agent N.A. Investigative [16]
12,13-DEHYDRO-8-O-ACETYLMANZAMINE A DMVP39I Discovery agent N.A. Investigative [17]
12,13-DEHYDROMANZAMINE A DM8XAWU Discovery agent N.A. Investigative [17]
3-(6-(phenylamino)-9H-purin-8-yl)benzonitrile DM8WL21 Discovery agent N.A. Investigative [18]
3-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione DM6T5K4 Discovery agent N.A. Investigative [19]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole DMN9YOB Discovery agent N.A. Investigative [20]
4-(5-bromo-1H-indol-3-yl)pyrimidin-2-amine DMJKUQI Discovery agent N.A. Investigative [7]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol DMSKJ1X Discovery agent N.A. Investigative [21]
6-deoxymanzamine X DMKPWN0 Discovery agent N.A. Investigative [17]
8-O-(4-bromobenzenesulfonyl)manzamine F DMDRPLA Discovery agent N.A. Investigative [17]
8-O-(4-chlorobenzenesulfonyl)manzamine F DM48JMC Discovery agent N.A. Investigative [17]
8-O-(4-toluenesulfonyl)manzamine A DM249GI Discovery agent N.A. Investigative [17]
8-OH-MANZAMINE A DM4QYEF Discovery agent N.A. Investigative [22]
9-N-ETHYL-8-ETHOXY-MANZAMINE A DMPXLEU Discovery agent N.A. Investigative [17]
9-N-METHYL-8-METHOXY-MANZAMINE A DM1YUBX Discovery agent N.A. Investigative [17]
alsterpaullone 2-cyanoethyl DMDI2KH Discovery agent N.A. Investigative [23]
AMP-PNP DMTOK1D Discovery agent N.A. Investigative [24]
AS-601245 DMQ95EB Discovery agent N.A. Investigative [25]
AZAKENPAULLONE DM61H07 Discovery agent N.A. Investigative [9]
Bisindolylmaleimide-I DMOQJZC Discovery agent N.A. Investigative [26]
BX-795 DMRIMLJ Discovery agent N.A. Investigative [27]
BX-912 DMZA45C Discovery agent N.A. Investigative [27]
CHIR-98014 DMVEBT6 Discovery agent N.A. Investigative [8]
CHIR-98023 DMFBW1H Discovery agent N.A. Investigative [7]
CI-1040 DMF3DZX Discovery agent N.A. Investigative [26]
CP-70949 DMBQTZG Diabetic complication 5A2Y Investigative [28]
CT-98024 DM6F8DM Discovery agent N.A. Investigative [13]
DM-204 DMSXI6W Solid tumour/cancer 2A00-2F9Z Investigative [28]
ELLAGIC ACID DMX8BS5 Discovery agent N.A. Investigative [29]
GSK-3beta inhibitor II DMQR7TZ Discovery agent N.A. Investigative [30]
GSK-3beta inhibitor XI DM734QB Discovery agent N.A. Investigative [31]
I-5 DM1TQ7N Discovery agent N.A. Investigative [32]
IM-12 DM58DGY Discovery agent N.A. Investigative [33]
indirubin deriv. 8a DMYLVQF Discovery agent N.A. Investigative [34]
K00244 DM2BKU8 Discovery agent N.A. Investigative [35]
L-779450 DM51B74 Discovery agent N.A. Investigative [36]
LEUCETTAMINE B DMFQEWM Discovery agent N.A. Investigative [37]
MANZAMINE A DMB3GNC Discovery agent N.A. Investigative [38]
Manzamine E DMOI9RT Discovery agent N.A. Investigative [22]
Manzamine Y DMC7ADZ N. A. N. A. Investigative [22]
N,8-diphenyl-9H-purin-6-amine DMZXF36 Discovery agent N.A. Investigative [18]
N-(6-(2-chlorophenyl)-1H-indazol-3-yl)butyramide DMDCX5O Discovery agent N.A. Investigative [16]
N-(6-(3-hydroxyphenyl)-1H-indazol-3-yl)butyramide DMKGBZA Discovery agent N.A. Investigative [16]
N-(6-(4-aminophenyl)-1H-indazol-3-yl)butyramide DMDQEZG Discovery agent N.A. Investigative [16]
N-(6-(4-fluorophenyl)-1H-indazol-3-yl)butyramide DM4M12J Discovery agent N.A. Investigative [16]
N-(6-(4-hydroxyphenyl)-1H-indazol-3-yl)butyramide DM8JLR4 Discovery agent N.A. Investigative [16]
N-(6-(furan-3-yl)-1H-indazol-3-yl)butyramide DMRGQTM Discovery agent N.A. Investigative [16]
N-(6-(pyridin-3-yl)-1H-indazol-3-yl)butyramide DM3FOKL Discovery agent N.A. Investigative [39]
N-(6-(pyridin-4-yl)-1H-indazol-3-yl)butyramide DM4GRK8 Discovery agent N.A. Investigative [16]
N-(6-(thiophen-3-yl)-1H-indazol-3-yl)butyramide DMNRSYP Discovery agent N.A. Investigative [16]
N-(6-(trifluoromethyl)-1H-indazol-3-yl)butyramide DMMHD9Z Discovery agent N.A. Investigative [16]
N-(6-benzyl-1H-indazol-3-yl)butyramide DM0OCLU Discovery agent N.A. Investigative [16]
N-(6-bromo-1H-indazol-3-yl)butyramide DMJPL7E Discovery agent N.A. Investigative [16]
N-(6-chloro-1H-indazol-3-yl)butyramide DMHGXPY Discovery agent N.A. Investigative [16]
N-(6-chloro-5-p-tolyl-1H-indazol-3-yl)butyramide DMIN128 Discovery agent N.A. Investigative [16]
N-(6-chloro-5-phenyl-1H-indazol-3-yl)butyramide DMJV3UO Discovery agent N.A. Investigative [39]
N-(6-phenethyl-1H-indazol-3-yl)butyramide DM9K4WP Discovery agent N.A. Investigative [16]
N-(6-phenyl-1H-indazol-3-yl)butyramide DMVCPLU Discovery agent N.A. Investigative [39]
N-(8-(3-cyanophenyl)-9H-purin-6-yl)pentanamide DMHFPE3 Discovery agent N.A. Investigative [18]
Neo-kauluamine DM6D0JC Discovery agent N.A. Investigative [22]
NU-6102 DMMOFKD Discovery agent N.A. Investigative [40]
PAULLONE DMQA8N3 Discovery agent N.A. Investigative [13]
PF-228 DM32FKD Discovery agent N.A. Investigative [41]
PMID19115845C89S DMB9F2L Discovery agent N.A. Investigative [42]
PYRAZOLOPYRIDAZINE 1 DMKTB5U Discovery agent N.A. Investigative [43]
PYRAZOLOPYRIDAZINE 2 DMI7AUJ Discovery agent N.A. Investigative [43]
Quinoxaline1 DMRWXH4 Discovery agent N.A. Investigative [23]
RGB-286147 DMP08BY Discovery agent N.A. Investigative [23]
Ro31-8220 DMDJLF0 Discovery agent N.A. Investigative [26]
SB-415286 DMMAL3I Discovery agent N.A. Investigative [7]
STAUROSPORINONE DMU2H4K Discovery agent N.A. Investigative [26]
Thieno analogue of kenpaullone DMIOTHG Discovery agent N.A. Investigative [9]
TWS-119 DMS29M4 Discovery agent N.A. Investigative [44]
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⏷ Show the Full List of 74 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Parkinson's disease 8A00.0 Substantia nigra tissue 1.26E-01 -0.23 -0.77
Alzheimer's disease 8A00.0 Entorhinal cortex 3.73E-01 -0.09 -0.24
Sarcoma 2C82 Muscle tissue 1.69E-12 -0.1 -0.2
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References

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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.
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6 Company report (Neurim Pharmaceuticals)
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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.
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