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)
• Synonyms: Serine/threonine-protein kinase GSK3B; GSK-3 beta
• Gene Name: GSK3B
• DTT Type: Clinical trial target; [1]
• Related Disease: Myotonic disorder [ICD-11: 8C71]
• BioChemical Class: Kinase
• UniProt ID: GSK3B_HUMAN
• TTD ID: T70977
• 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

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	Fragile X syndrome	LD55	Phase 2	[4]
LY2090314	DMTBFE4	Acute myeloid leukaemia	2A60	Phase 2	[5], [6]
Tideglusib	DME4LA1	Osteosarcoma	2B51	Phase 2	[1]
Neu-120	DMXKOUC	Parkinson disease	8A00.0	Phase 1/2	[7]

5 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AR-A014418	DMUPN01	Ovarian cancer	2C73	Patented	[8]
CHIR-99021	DMB8MNU	Allergic inflammation	4A80-4A85	Patented	[9]
KENPAULLONE	DMAGVXW	Discovery agent	N.A.	Patented	[10]
PMID26161698-Compound-18	DM6JVR5	N. A.	N. A.	Patented	[11]
TDZD-8	DMG6Q45	Malignant glioma	2A00.0	Patented	[12]

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	[13]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[14]
SAN-61	DMGUA9Y	Alzheimer disease	8A20	Terminated	[15]

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	[16]
(E)-N-(6-(prop-1-enyl)-1H-indazol-3-yl)butyramide	DMHKXPM	Discovery agent	N.A.	Investigative	[17]
12,13-DEHYDRO-8-O-ACETYLMANZAMINE A	DMVP39I	Discovery agent	N.A.	Investigative	[18]
12,13-DEHYDROMANZAMINE A	DM8XAWU	Discovery agent	N.A.	Investigative	[18]
3-(6-(phenylamino)-9H-purin-8-yl)benzonitrile	DM8WL21	Discovery agent	N.A.	Investigative	[19]
3-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione	DM6T5K4	Discovery agent	N.A.	Investigative	[20]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[21]
4-(5-bromo-1H-indol-3-yl)pyrimidin-2-amine	DMJKUQI	Discovery agent	N.A.	Investigative	[8]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[22]
6-deoxymanzamine X	DMKPWN0	Discovery agent	N.A.	Investigative	[18]
8-O-(4-bromobenzenesulfonyl)manzamine F	DMDRPLA	Discovery agent	N.A.	Investigative	[18]
8-O-(4-chlorobenzenesulfonyl)manzamine F	DM48JMC	Discovery agent	N.A.	Investigative	[18]
8-O-(4-toluenesulfonyl)manzamine A	DM249GI	Discovery agent	N.A.	Investigative	[18]
8-OH-MANZAMINE A	DM4QYEF	Discovery agent	N.A.	Investigative	[23]
9-N-ETHYL-8-ETHOXY-MANZAMINE A	DMPXLEU	Discovery agent	N.A.	Investigative	[18]
9-N-METHYL-8-METHOXY-MANZAMINE A	DM1YUBX	Discovery agent	N.A.	Investigative	[18]
alsterpaullone 2-cyanoethyl	DMDI2KH	Discovery agent	N.A.	Investigative	[24]
AMP-PNP	DMTOK1D	Discovery agent	N.A.	Investigative	[25]
AS-601245	DMQ95EB	Discovery agent	N.A.	Investigative	[26]
AZAKENPAULLONE	DM61H07	Discovery agent	N.A.	Investigative	[10]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[27]
BX-795	DMRIMLJ	Discovery agent	N.A.	Investigative	[28]
BX-912	DMZA45C	Discovery agent	N.A.	Investigative	[28]
CHIR-98014	DMVEBT6	Discovery agent	N.A.	Investigative	[9]
CHIR-98023	DMFBW1H	Discovery agent	N.A.	Investigative	[8]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[27]
CP-70949	DMBQTZG	Diabetic complication	5A2Y	Investigative	[29]
CT-98024	DM6F8DM	Discovery agent	N.A.	Investigative	[14]
DM-204	DMSXI6W	Solid tumour/cancer	2A00-2F9Z	Investigative	[29]
ELLAGIC ACID	DMX8BS5	Discovery agent	N.A.	Investigative	[30]
GSK-3beta inhibitor II	DMQR7TZ	Discovery agent	N.A.	Investigative	[31]
GSK-3beta inhibitor XI	DM734QB	Discovery agent	N.A.	Investigative	[32]
I-5	DM1TQ7N	Discovery agent	N.A.	Investigative	[33]
IM-12	DM58DGY	Discovery agent	N.A.	Investigative	[34]
indirubin deriv. 8a	DMYLVQF	Discovery agent	N.A.	Investigative	[35]
K00244	DM2BKU8	Discovery agent	N.A.	Investigative	[36]
L-779450	DM51B74	Discovery agent	N.A.	Investigative	[37]
LEUCETTAMINE B	DMFQEWM	Discovery agent	N.A.	Investigative	[38]
MANZAMINE A	DMB3GNC	Discovery agent	N.A.	Investigative	[39]
Manzamine E	DMOI9RT	Discovery agent	N.A.	Investigative	[23]
Manzamine Y	DMC7ADZ	N. A.	N. A.	Investigative	[23]
N,8-diphenyl-9H-purin-6-amine	DMZXF36	Discovery agent	N.A.	Investigative	[19]
N-(6-(2-chlorophenyl)-1H-indazol-3-yl)butyramide	DMDCX5O	Discovery agent	N.A.	Investigative	[17]
N-(6-(3-hydroxyphenyl)-1H-indazol-3-yl)butyramide	DMKGBZA	Discovery agent	N.A.	Investigative	[17]
N-(6-(4-aminophenyl)-1H-indazol-3-yl)butyramide	DMDQEZG	Discovery agent	N.A.	Investigative	[17]
N-(6-(4-fluorophenyl)-1H-indazol-3-yl)butyramide	DM4M12J	Discovery agent	N.A.	Investigative	[17]
N-(6-(4-hydroxyphenyl)-1H-indazol-3-yl)butyramide	DM8JLR4	Discovery agent	N.A.	Investigative	[17]
N-(6-(furan-3-yl)-1H-indazol-3-yl)butyramide	DMRGQTM	Discovery agent	N.A.	Investigative	[17]
N-(6-(pyridin-3-yl)-1H-indazol-3-yl)butyramide	DM3FOKL	Discovery agent	N.A.	Investigative	[40]
N-(6-(pyridin-4-yl)-1H-indazol-3-yl)butyramide	DM4GRK8	Discovery agent	N.A.	Investigative	[17]
N-(6-(thiophen-3-yl)-1H-indazol-3-yl)butyramide	DMNRSYP	Discovery agent	N.A.	Investigative	[17]
N-(6-(trifluoromethyl)-1H-indazol-3-yl)butyramide	DMMHD9Z	Discovery agent	N.A.	Investigative	[17]
N-(6-benzyl-1H-indazol-3-yl)butyramide	DM0OCLU	Discovery agent	N.A.	Investigative	[17]
N-(6-bromo-1H-indazol-3-yl)butyramide	DMJPL7E	Discovery agent	N.A.	Investigative	[17]
N-(6-chloro-1H-indazol-3-yl)butyramide	DMHGXPY	Discovery agent	N.A.	Investigative	[17]
N-(6-chloro-5-p-tolyl-1H-indazol-3-yl)butyramide	DMIN128	Discovery agent	N.A.	Investigative	[17]
N-(6-chloro-5-phenyl-1H-indazol-3-yl)butyramide	DMJV3UO	Discovery agent	N.A.	Investigative	[40]
N-(6-phenethyl-1H-indazol-3-yl)butyramide	DM9K4WP	Discovery agent	N.A.	Investigative	[17]
N-(6-phenyl-1H-indazol-3-yl)butyramide	DMVCPLU	Discovery agent	N.A.	Investigative	[40]
N-(8-(3-cyanophenyl)-9H-purin-6-yl)pentanamide	DMHFPE3	Discovery agent	N.A.	Investigative	[19]
Neo-kauluamine	DM6D0JC	Discovery agent	N.A.	Investigative	[23]
NU-6102	DMMOFKD	Discovery agent	N.A.	Investigative	[41]
PAULLONE	DMQA8N3	Discovery agent	N.A.	Investigative	[14]
PF-228	DM32FKD	Discovery agent	N.A.	Investigative	[42]
PMID19115845C89S	DMB9F2L	Discovery agent	N.A.	Investigative	[43]
PYRAZOLOPYRIDAZINE 1	DMKTB5U	Discovery agent	N.A.	Investigative	[44]
PYRAZOLOPYRIDAZINE 2	DMI7AUJ	Discovery agent	N.A.	Investigative	[44]
Quinoxaline1	DMRWXH4	Discovery agent	N.A.	Investigative	[24]
RGB-286147	DMP08BY	Discovery agent	N.A.	Investigative	[24]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[27]
SB-415286	DMMAL3I	Discovery agent	N.A.	Investigative	[8]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[27]
Thieno analogue of kenpaullone	DMIOTHG	Discovery agent	N.A.	Investigative	[10]
TWS-119	DMS29M4	Discovery agent	N.A.	Investigative	[45]

Molecular Expression Atlas (MEA) 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

References

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