glycogen synthase kinase 3 beta

Target id: 2030

Nomenclature: glycogen synthase kinase 3 beta

Abbreviated Name: GSK3B

Family: GSK subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for glycogen synthase kinase 3 beta in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 420 3q13.3 GSK3B glycogen synthase kinase 3 beta
Mouse - 420 16 B4 Gsk3b glycogen synthase kinase 3 beta
Rat - 420 11 q21 Gsk3b glycogen synthase kinase 3 beta
Previous and Unofficial Names
GSK3 | GSK-3 beta | tau phosphorylating kinase I [18]
Database Links
BRENDA
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  GSK-3 Beta complexed with Indirubin-3'-monoxime
PDB Id:  1Q41
Resolution:  2.1Å
Species:  Human
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  STRUCTURE OF GLYCOGEN SYNTHASE KINASE-3 (GSK3B)
PDB Id:  1I09
Resolution:  2.7Å
Species:  Human
References:  32
Enzyme Reaction
EC Number: 2.7.11.26

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
AZD2858 Hs Inhibition 8.3 pKi 3
pKi 8.3 (Ki 4.9x10-9 M) [3]
GSK-3 inhibitor XIII Hs Inhibition 7.7 pKi 2
pKi 7.7 (Ki 2.2x10-8 M) [2]
GSK-3beta inhibitor XI Oc Inhibition 7.6 pKi 26
pKi 7.6 (Ki 2.5x10-8 M) [26]
AZD1080 Hs Inhibition 7.5 pKi 17
pKi 7.5 (Ki 3.1x10-8 M) [17]
GSK-3beta inhibitor VIII Hs Inhibition 7.4 pKi 5
pKi 7.4 (Ki 3.8x10-8 M) [5]
tideglusib Hs Irreversible inhibition 7.3 pKi 11
pKi 7.3 (Ki 5x10-8 M) [11]
CHIR-98014 Hs Inhibition 9.2 pIC50 28
pIC50 9.2 (IC50 5.8x10-10 M) [28]
alsterpaullone 2-cyanoethyl Hs Inhibition 9.1 pIC50 14
pIC50 9.1 (IC50 8x10-10 M) [14]
LY2090314 Hs Inhibition 9.0 pIC50 13
pIC50 9.0 (IC50 1.1x10-9 M) [13]
Description: Inhibition of GSK-3β-mediated phosphoryaltion of phosph0-CREB
RGB-286638 Hs Inhibition 8.5 pIC50 6
pIC50 8.5 (IC50 3x10-9 M) [6]
alsterpaullone Hs Inhibition 8.4 pIC50 22
pIC50 8.4 (IC50 4x10-9 M) [22]
GSK-3 inhibitor IX Pig Inhibition 8.3 pIC50 23,27
pIC50 8.3 (IC50 5x10-9 M) [23,27]
Description: GSK3α/β complex from pig brain
CHIR-99021 Hs Inhibition 8.2 pIC50 28
pIC50 8.2 (IC50 6.7x10-9 M) [28]
SB 216763 Hs Inhibition ~8.1 pIC50 8
pIC50 ~8.1 (IC50 ~9x10-9 M) [8]
GSK-3 inhibitor X Pig Inhibition 8.0 pIC50 27
pIC50 8.0 (IC50 1x10-8 M) [27]
Description: Measured using GSK3 as a complex of α and β isozymes, isolated from pig brain
compound 2 [PMID: 22560567] Hs Inhibition 7.8 pIC50 7
pIC50 7.8 (IC50 1.72x10-8 M) [7]
1-azakenpaullone Hs Inhibition 7.7 pIC50 20
pIC50 7.7 (IC50 1.8x10-8 M) [20]
indirubin-3'-monoxime Hs Inhibition 7.7 pIC50 21
pIC50 7.7 (IC50 2.2x10-8 M) [21]
kenpaullone Hs Inhibition 7.6 pIC50 21
pIC50 7.6 (IC50 2.3x10-8 M) [21]
compound 52 [PMID: 9677190] Hs Inhibition 7.5 pIC50 14
pIC50 7.5 (IC50 3x10-8 M) [14]
TWS119 Hs Inhibition 7.5 pIC50 10
pIC50 7.5 (IC50 3x10-8 M) [10]
SB-415286 Hs Inhibition ~7.4 pIC50 8
pIC50 ~7.4 (IC50 ~3.8x10-8 M) [8]
IM-12 Hs Inhibition 7.3 pIC50 30
pIC50 7.3 (IC50 5.3x10-8 M) [30]
compound 89S [PMID: 19115845] Hs Inhibition 6.8 pIC50 24
pIC50 6.8 (IC50 1.46x10-7 M) [24]
compound 4g [PMID: 2680437] Hs Inhibition 6.7 pIC50 31
pIC50 6.7 (IC50 1.9x10-7 M) [31]
Description: Evaluated in a Kinase-Glo assay.
compound 5b [PMID: 24900464] Hs Inhibition 6.6 pIC50 12
pIC50 6.6 (IC50 2.5x10-7 M) [12]
GSK-3beta inhibitor II Hs Inhibition 6.4 pIC50 25
pIC50 6.4 (IC50 3.9x10-7 M) [25]
isogranulatimide Hs Inhibition 6.3 pIC50 14,19
pIC50 6.3 (IC50 5x10-7 M) [14,19]
7-hydroxystaurosporine Hs Inhibition 6.3 pIC50 19
pIC50 6.3 (IC50 5x10-7 M) [19]
BX-795 Hs Inhibition 6.2 pIC50 15
pIC50 6.2 (IC50 6.2x10-7 M) [15]
Cdk/Crk inhibitor Hs Inhibition 6.1 pIC50 14
pIC50 6.1 (IC50 7.54x10-7 M) [14]
Cdk1/5 inhibitor Hs Inhibition 6.0 pIC50 14
pIC50 6.0 (IC50 1x10-6 M) [14]
GSK-3beta inhibitor I Hs Inhibition 5.8 pIC50 35
pIC50 5.8 (IC50 1.4x10-6 M) [35]
BX-912 Hs Inhibition 5.1 pIC50 15
pIC50 5.1 (IC50 7.4x10-6 M) [15]
Li+ Hs Inhibition 2.6 pIC50 29
pIC50 2.6 (IC50 2.5x10-3 M) Competive with Mg2+ [29]
View species-specific inhibitor tables
Inhibitor Comments
GSK3β may be the primary target of the approved drug lithium, which inhibits GSK3β activity by approximately 80% [33].
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 9,34

Key to terms and symbols Click column headers to sort
Target used in screen: GSK3B
Ligand Sp. Type Action Affinity Units
enzastaurin Hs Inhibitor Inhibition 8.1 pKd
AT-7519 Hs Inhibitor Inhibition 8.0 pKd
BMS-387032 Hs Inhibitor Inhibition 7.4 pKd
staurosporine Hs Inhibitor Inhibition 7.2 pKd
GSK690693 Hs Inhibitor Inhibition 7.0 pKd
tamatinib Hs Inhibitor Inhibition 6.9 pKd
R547 Hs Inhibitor Inhibition 6.6 pKd
A-674563 Hs Inhibitor Inhibition 6.5 pKd
dovitinib Hs Inhibitor Inhibition 6.5 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,16

Key to terms and symbols Click column headers to sort
Target used in screen: GSK3β/GSK3b
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
alsterpaullone Hs Inhibitor Inhibition 2.7 -1.0 3.0
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 2.7 -3.0 0.0
GSK-3 inhibitor IX Hs Inhibitor Inhibition 3.8 -1.0 0.0
staurosporine Hs Inhibitor Inhibition 4.4 7.5 4.5
SB 218078 Hs Inhibitor Inhibition 4.6 40.0 23.0
JNK inhibitor V Hs Inhibitor Inhibition 6.2 8.0 1.0
PKR inhibitor Hs Inhibitor Inhibition 6.3 4.0 0.0
GF109203X Hs Inhibitor Inhibition 7.0 24.0 3.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 9.0 4.0 0.0
Ro-32-0432 Hs Inhibitor Inhibition 11.2
Displaying the top 10 most potent ligands  View all ligands in screen »

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol.29 (11): 1039-45. [PMID:22037377]

2. Bebbington D, Binch H, Charrier JD, Everitt S, Fraysse D, Golec J, Kay D, Knegtel R, Mak C, Mazzei F et al.. (2009) The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg. Med. Chem. Lett.19 (13): 3586-92. [PMID:19447622]

3. Berg S, Bergh M, Hellberg S, Högdin K, Lo-Alfredsson Y, Söderman P, von Berg S, Weigelt T, Ormö M, Xue Y et al.. (2012) Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines. J. Med. Chem.55 (21): 9107-19. [PMID:22489897]

4. Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M. (2003) Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. J. Mol. Biol.333 (2): 393-407. [PMID:14529625]

5. Bhat R, Xue Y, Berg S, Hellberg S, Ormö M, Nilsson Y, Radesäter AC, Jerning E, Markgren PO, Borgegård T et al.. (2003) Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J. Biol. Chem.278 (46): 45937-45. [PMID:12928438]

6. Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, Hu Y, Mimura N, Cottini F, Gorgun G et al.. (2013) Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia27 (12): 2366-75. [PMID:23807770]

7. Coffman K, Brodney M, Cook J, Lanyon L, Pandit J, Sakya S, Schachter J, Tseng-Lovering E, Wessel M. (2011) 6-amino-4-(pyrimidin-4-yl)pyridones: novel glycogen synthase kinase-3β inhibitors. Bioorg. Med. Chem. Lett.21 (5): 1429-33. [PMID:21295469]

8. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L et al.. (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol.7 (10): 793-803. [PMID:11033082]

9. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol.29 (11): 1046-51. [PMID:22037378]

10. Ding S, Wu TY, Brinker A, Peters EC, Hur W, Gray NS, Schultz PG. (2003) Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. U.S.A.100 (13): 7632-7. [PMID:12794184]

11. Domínguez JM, Fuertes A, Orozco L, del Monte-Millán M, Delgado E, Medina M. (2012) Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J. Biol. Chem.287 (2): 893-904. [PMID:22102280]

12. Dowling JE, Chuaqui C, Pontz TW, Lyne PD, Larsen NA, Block MH, Chen H, Su N, Wu A, Russell D et al.. (2012) Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization. ACS Med Chem Lett3 (4): 278-83. [PMID:24900464]

13. Engler TA, Henry JR, Malhotra S, Cunningham B, Furness K, Brozinick J, Burkholder TP, Clay MP, Clayton J, Diefenbacher C et al.. (2004) Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4-(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3. J. Med. Chem.47 (16): 3934-7. [PMID:15267232]

14. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. U.S.A.104 (51): 20523-8. [PMID:18077363]

15. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S et al.. (2005) Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J. Biol. Chem.280 (20): 19867-74. [PMID:15772071]

16. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J.451 (2): 313-28. [PMID:23398362]

17. Georgievska B, Sandin J, Doherty J, Mörtberg A, Neelissen J, Andersson A, Gruber S, Nilsson Y, Schött P, Arvidsson PI et al.. (2013) AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J. Neurochem.125 (3): 446-56. [PMID:23410232]

18. Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K. (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett.325 (3): 167-72. [PMID:7686508]

19. Jiang X, Zhao B, Britton R, Lim LY, Leong D, Sanghera JS, Zhou BB, Piers E, Andersen RJ, Roberge M. (2004) Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide. Mol. Cancer Ther.3 (10): 1221-7. [PMID:15486189]

20. Kunick C, Lauenroth K, Leost M, Meijer L, Lemcke T. (2004) 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta. Bioorg. Med. Chem. Lett.14 (2): 413-6. [PMID:14698171]

21. Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM et al.. (2001) Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?. J. Biol. Chem.276 (1): 251-60. [PMID:11013232]

22. Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM, Bibb JA, Snyder GL, Greengard P, Zaharevitz DW et al.. (2000) Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur. J. Biochem.267 (19): 5983-94. [PMID:10998059]

23. Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R et al.. (2003) GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem. Biol.10 (12): 1255-66. [PMID:14700633]

24. Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Bossi R, Ciavolella A, Cirla A, Cristiani C, Croci V, D'Alessio R et al.. (2009) First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J. Med. Chem.52 (2): 293-307. [PMID:19115845]

25. Naerum L, Nørskov-Lauritsen L, Olesen PH. (2002) Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors. Bioorg. Med. Chem. Lett.12 (11): 1525-8. [PMID:12031334]

26. O'Neill DJ, Shen L, Prouty C, Conway BR, Westover L, Xu JZ, Zhang HC, Maryanoff BE, Murray WV, Demarest KT et al.. (2004) 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.12 (12): 3167-85. [PMID:15158785]

27. Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A, Musacchio A, Roe SM, Pearl L, Leost M et al.. (2004) Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J. Med. Chem.47 (4): 935-46. [PMID:14761195]

28. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T et al.. (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes52 (3): 588-95. [PMID:12606497]

29. Ryves WJ, Harwood AJ. (2001) Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem. Biophys. Res. Commun.280 (3): 720-5. [PMID:11162580]

30. Schmöle AC, Brennführer A, Karapetyan G, Jaster R, Pews-Davtyan A, Hübner R, Ortinau S, Beller M, Rolfs A, Frech MJ. (2010) Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells. Bioorg. Med. Chem.18 (18): 6785-95. [PMID:20708937]

31. Tantray MA, Khan I, Hamid H, Alam MS, Umar S, Ali Y, Sharma K, Hussain F. (2016) Synthesis of Novel Oxazolo[4,5-b]pyridine-2-one based 1,2,3-triazoles as Glycogen Synthase Kinase-3β Inhibitors with Anti-inflammatory Potential. Chem Biol Drug Des87 (6): 918-26. [PMID:26804375]

32. ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson L, Jain J. (2001) Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat. Struct. Biol.8 (7): 593-6. [PMID:11427888]

33. Werstuck GH, Kim AJ, Brenstrum T, Ohnmacht SA, Panna E, Capretta A. (2004) Examining the correlations between GSK-3 inhibitory properties and anti-convulsant efficacy of valproate and valproate-related compounds. Bioorg. Med. Chem. Lett.14 (22): 5465-7. [PMID:15482904]

34. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol.17 (11): 1241-9. [PMID:21095574]

35. Zhang P, Hu HR, Huang ZH, Lei JY, Chu Y, Ye DY. (2012) Identification of novel scaffold of benzothiazepinones as non-ATP competitive glycogen synthase kinase-3β inhibitors through virtual screening. Bioorg. Med. Chem. Lett.22 (23): 7232-6. [PMID:23099099]

How to cite this page

GSK subfamily: glycogen synthase kinase 3 beta. Last modified on 26/07/2017. Accessed on 19/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2030.