Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRZQE3)

• DTT Name: Glycogen synthase kinase-3 alpha (GSK-3A)
• Synonyms: Serine/threonineprotein kinase GSK3A; Serine/threonine-protein kinase GSK3A; Glycogen synthase kinase3 alpha; Glycogen synthase kinase 3; GSK3 alpha; GSK-3 alpha; GSK-3
• Gene Name: GSK3A
• DTT Type: Successful target; [1]
• Related Disease: Epilepsy/seizure [ICD-11: 8A61-8A6Z]
• BioChemical Class: Kinase
• UniProt ID: GSK3A_HUMAN
• TTD ID: T76910
• EC Number: EC 2.7.11.26
• Sequence:
  MSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGV
  GASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQGPERSQEVAYT
  DIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFY
  SSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGV
  CHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSS
  IDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIK
  AHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPLP
  PLFNFSAGELSIQPSLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLT
  NSS
• Function: Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. 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), CTNNB1/beta-catenin, APC and AXIN1.
• KEGG Pathway:
  Chemokine signaling pathway (hsa04062)
  Dopaminergic synapse (hsa04728)
  Non-alcoholic fatty liver disease (hsa04932)
  Shigellosis (hsa05131)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[1], [2]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lithium	DMZ3OU6	Fragile X syndrome	LD55	Phase 2	[3]
LY2090314	DMTBFE4	Acute myeloid leukaemia	2A60	Phase 2	[4], [5]

29 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AR-A014418	DMUPN01	Ovarian cancer	2C73	Patented	[4]
CHIR-99021	DMB8MNU	Allergic inflammation	4A80-4A85	Patented	[4]
Indazole derivative 6	DMGO1CB	N. A.	N. A.	Patented	[4]
Indirubin derivative 2	DMLX183	N. A.	N. A.	Patented	[4]
KENPAULLONE	DMAGVXW	Discovery agent	N.A.	Patented	[4]
Maleimides derivative 1	DMINM8F	N. A.	N. A.	Patented	[4]
Maleimides derivative 2	DMUVYWE	N. A.	N. A.	Patented	[4]
Maleimides derivative 3	DMEFQND	N. A.	N. A.	Patented	[4]
N-naphtyl-N-benzylurea derivative 1	DMCVBPF	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-15	DM3G21F	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-16	DM9VXY7	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-17	DMR7V9E	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-18	DMNR6KL	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-19	DM8V7QH	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-20	DMDA3PN	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-21	DMO1NAR	N. A.	N. A.	Patented	[4]
PMID27828716-Compound-BIO-acetoxime	DMUM5L6	Malignant glioma	2A00.0	Patented	[4]
Pyrazole and benzimidazole derivative 1	DM05S2X	N. A.	N. A.	Patented	[4]
Pyrazolodihydropyridine derivative 1	DMKYX7J	N. A.	N. A.	Patented	[4]
Quinoline derivative 14	DMSRB8M	N. A.	N. A.	Patented	[4]
Quinoline derivative 15	DM7HD0T	N. A.	N. A.	Patented	[4]
Quinolinyl pyrazinyl urea derivative 1	DMCIKR3	N. A.	N. A.	Patented	[4]
Quinolinyl pyrazinyl urea derivative 2	DMKJN9G	N. A.	N. A.	Patented	[4]
Spiroquinolone derivative 1	DMYJL2Z	N. A.	N. A.	Patented	[4]
TDZD-8	DMG6Q45	Malignant glioma	2A00.0	Patented	[4]
Thiadiazolidindione derivative 1	DM1L3ZA	N. A.	N. A.	Patented	[4]
Thiadiazolidindione derivative 2	DM5AUL0	N. A.	N. A.	Patented	[4]
Thiadiazolidindione derivative 3	DMNTZ93	N. A.	N. A.	Patented	[4]
Tricyclic 5-quinolone derivative 1	DMYEDJI	N. A.	N. A.	Patented	[4]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
6-bromoindirubin-3-oxime	DM12WYV	Discovery agent	N.A.	Investigative	[6]
AR-534	DMNJ632	Discovery agent	N.A.	Investigative	[7]
Benzofuran-3-yl-(indol-3-yl)maleimides	DMNVG1M	Discovery agent	N.A.	Investigative	[8]
Lithium chloride	DMHYLQ2	Discovery agent	N.A.	Investigative	[9], [10]
SB216763	DMIYFQ5	Discovery agent	N.A.	Investigative	[11], [12], [13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Sarcoma	2C82	Muscle tissue	4.67E-06	0.02	0.06

References

• [1] Challenges and new opportunities in the investigation of new drug therapies to treat frontotemporal dementia. Expert Opin Ther Targets. 2008 Nov;12(11):1367-76.
• [2] Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43.
• [3] 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.
• [4] Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015).Expert Opin Ther Pat. 2017 Jun;27(6):657-666.
• [5] Activating the Wnt/beta-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS One. 2015 Apr 27;10(4):e0125028.
• [6] Stable generation of serum- and feeder-free embryonic stem cell-derived mice with full germline-competency by using a GSK3 specific inhibitor. Genesis. 2009 Jun;47(6):414-22.
• [7] A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest. 2009 May;119(5):1382-95.
• [8] From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3beta inhibitors that suppress proliferation and survival of pancreatic cancer cells. J Med Chem. 2009 Apr 9;52(7):1853-63.
• [9] Glycogen synthase kinase 3 beta (GSK-3 beta) as a therapeutic target in neuroAIDS. J Neuroimmune Pharmacol. 2007 Mar;2(1):93-6.
• [10] Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med. 2002 Mar;8(3):126-32.
• [11] Intracellular protein phosphorylation in eosinophils and the functional relevance in cytokine production. Int Arch Allergy Immunol. 2009;149 Suppl 1:45-50.
• [12] Cocaine-induced hyperactivity and sensitization are dependent on GSK3. Neuropharmacology. 2009 Jun;56(8):1116-23.
• [13] The ceiling effect of pharmacological postconditioning with the phytoestrogen genistein is reversed by the GSK3beta inhibitor SB 216763 [3-(2,4-dic... J Pharmacol Exp Ther. 2009 Jun;329(3):1134-41.