Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQWAU1)

• DTT Name: GSK3A messenger RNA (GSK3A mRNA)
• Synonyms: Serine/threonineprotein kinase GSK3A (mRNA); Serine/threonine-protein kinase GSK3A (mRNA); Glycogen synthase kinase3 alpha (mRNA); Glycogen synthase kinase 3 (mRNA); GSK3 alpha (mRNA); GSK-3 alpha (mRNA); GSK-3 (mRNA)
• Gene Name: GSK3A
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: GSK3A_HUMAN
• TTD ID: T85250
• 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 (NAFLD) (hsa04932)
• 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

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
aloisine A	DM5U1LN	Discovery agent	N.A.	Investigative	[2]
CHIR-98014	DMVEBT6	Discovery agent	N.A.	Investigative	[1]
indirubin deriv. 8a	DMYLVQF	Discovery agent	N.A.	Investigative	[3]
ISIS 116625	DMIJES1	Discovery agent	N.A.	Investigative	[4]
ISIS 116631	DM2X5RT	Discovery agent	N.A.	Investigative	[4]
ISIS 116632	DMW2Q4T	Discovery agent	N.A.	Investigative	[4]
ISIS 116648	DMUOB3S	Discovery agent	N.A.	Investigative	[4]
ISIS 116654	DMBJU2X	Discovery agent	N.A.	Investigative	[4]
ISIS 116670	DM9R51M	Discovery agent	N.A.	Investigative	[4]
LEUCETTAMINE B	DMFQEWM	Discovery agent	N.A.	Investigative	[5]

References

• [1] 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.
• [2] Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J Med Chem. 2003 Jan 16;46(2):222-36.
• [3] 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.
• [4] US patent application no. 6,316,259, Antisense inhibition of glycogen synthase kinase 3 alpha expression.
• [5] 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.