AKT serine/threonine kinase 2 | Akt (Protein kinase B, PKB) family | IUPHAR/BPS Guide to PHARMACOLOGY

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AKT serine/threonine kinase 2

Target not currently curated in GtoImmuPdb

Target id: 1480

Nomenclature: AKT serine/threonine kinase 2

Abbreviated Name: Akt2

Family: Akt (Protein kinase B, PKB) family

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

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 481 19q13.1-q13.2 AKT2 AKT serine/threonine kinase 2
Mouse - 481 7 B1 Akt2 thymoma viral proto-oncogene 2
Rat - 481 1q22 Akt2 AKT serine/threonine kinase 2
Previous and Unofficial Names
AKT2 kinase | PKB beta | RAC protein kinase beta RAC-PK beta | RAC-PK-beta | protein kinase B beta | PKB2 | RAC-beta serine/threonine-protein kinase | v-akt murine thymoma viral oncogene homolog 2
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  STRUCTURE OF PROTEIN KINASE B UNPHOSPHORYLATED
PDB Id:  1GZO
Resolution:  2.75Å
Species:  Human
References:  17
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human Akt2 in complex with GSK690693
PDB Id:  3D0E
Ligand:  GSK690693
Resolution:  2.0Å
Species:  Human
References:  8
Enzyme Reaction
EC Number: 2.7.11.11

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 Value Parameter Reference
A-443654 Hs Inhibition ~9.8 pKi 12
pKi ~9.8 (Ki ~1.6x10-10 M) [12]
uprosertib Hs Inhibition 8.9 pKi 6
pKi 8.9 (Ki 1.4x10-9 M) [6]
afuresertib Hs Inhibition 8.7 pKi 6
pKi 8.7 (Ki 2x10-9 M) [6]
PHT-427 Hs Inhibition 5.6 pKi 13
pKi 5.6 (Ki 2.67x10-6 M) [13]
Description: Assay using purified recombinant pleckstrin homology domain of human Akt2
compound E22 [PMID: 31298542] Hs Inhibition 8.9 pIC50 5
pIC50 8.9 (IC50 1.2x10-9 M) [5]
capivasertib Hs Inhibition 8.1 pIC50 1
pIC50 8.1 (IC50 8x10-9 M) [1]
compound 1 [PMID: 20005102] Hs Inhibition 7.9 pIC50 10
pIC50 7.9 (IC50 1.2x10-8 M) [10]
GSK690693 Hs Inhibition 7.9 pIC50 8
pIC50 7.9 (IC50 1.3x10-8 M) [8]
ipatasertib Hs Inhibition 7.7 pIC50 3
pIC50 7.7 (IC50 1.8x10-8 M) [3]
Inhibitor Comments
Note that A-443654 has similar potency across all three Akt isoforms [12].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
miransertib Hs Inhibition 8.4 pIC50 9
pIC50 8.4 (IC50 4.5x10-9 M) [9]
MK-2206 Hs Negative 7.9 pIC50 15-16
pIC50 7.9 (IC50 1.2x10-8 M) [15-16]
Akt inhibitor VIII Hs Negative 6.7 pIC50 11
pIC50 6.7 (IC50 2.1x10-7 M) [11]
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: 4,14

Key to terms and symbols Click column headers to sort
Target used in screen: AKT2
Ligand Sp. Type Action Value Parameter
GSK690693 Hs Inhibitor Inhibition 8.7 pKd
staurosporine Hs Inhibitor Inhibition 7.4 pKd
midostaurin Hs Inhibitor Inhibition 6.1 pKd
lestaurtinib Hs Inhibitor Inhibition 5.7 pKd
sunitinib Hs Inhibitor Inhibition 5.6 pKd
A-674563 Hs Inhibitor Inhibition 5.5 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
crizotinib Hs Inhibitor Inhibition <5.5 pKd
linifanib Hs Inhibitor Inhibition <5.5 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: 2,7

Key to terms and symbols Click column headers to sort
Target used in screen: PKBβ/AKT2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 5.5 5.0 1.5
SB 218078 Hs Inhibitor Inhibition 48.5 101.0 92.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 55.8 133.0 44.0
H-89 Hs Inhibitor Inhibition 75.4 86.0 36.0
midostaurin Hs Inhibitor Inhibition 77.2 80.0 46.0
TGF-beta RI inhibitor III Hs Inhibitor Inhibition 80.1 115.0 95.0
AG1478 Hs Inhibitor Inhibition 84.1 128.0 93.0
K-252a Hs Inhibitor Inhibition 84.2 67.0 22.0
AG 1296 Hs Inhibitor Inhibition 86.7 111.0 83.0
SU11652 Hs Inhibitor Inhibition 86.9 91.0 33.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Disease:  Familial partial lipodystrophy due to AKT2 mutations
Synonyms: Familial partial lipodystrophy [Disease Ontology: DOID:0050440]
Disease Ontology: DOID:0050440
Orphanet: ORPHA79085
Drugs: 
Disease:  Hypoinsulinemic hypoglycemia with hemihypertrophy
OMIM: 240900
Orphanet: ORPHA293964

References

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1. Addie M, Ballard P, Buttar D, Crafter C, Currie G, Davies BR, Debreczeni J, Dry H, Dudley P, Greenwood R et al.. (2013) Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases. J. Med. Chem., 56 (5): 2059-73. [PMID:23394218]

2. 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]

3. Blake JF, Xu R, Bencsik JR, Xiao D, Kallan NC, Schlachter S, Mitchell IS, Spencer KL, Banka AL, Wallace EM et al.. (2012) Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J. Med. Chem., 55 (18): 8110-27. [PMID:22934575]

4. 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]

5. Dong X, Zhan W, Zhao M, Che J, Dai X, Wu Y, Xu L, Zhou Y, Zhao Y, Tian T et al.. (2019) Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design. J. Med. Chem., 62 (15): 7264-7288. [PMID:31298542]

6. Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA et al.. (2014) Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS ONE, 9 (6): e100880. [PMID:24978597]

7. 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]

8. Heerding DA, Rhodes N, Leber JD, Clark TJ, Keenan RM, Lafrance LV, Li M, Safonov IG, Takata DT, Venslavsky JW et al.. (2008) Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J. Med. Chem., 51 (18): 5663-79. [PMID:18800763]

9. Lapierre JM, Eathiraj S, Vensel D, Liu Y, Bull CO, Cornell-Kennon S, Iimura S, Kelleher EW, Kizer DE, Koerner S et al.. (2016) Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. J. Med. Chem., 59 (13): 6455-69. [PMID:27305487]

10. Lin H, Yamashita DS, Zeng J, Xie R, Verma S, Luengo JI, Rhodes N, Zhang S, Robell KA, Choudhry AE et al.. (2010) 2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg. Med. Chem. Lett., 20 (2): 679-83. [PMID:20005102]

11. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE et al.. (2005) Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett., 15 (3): 761-4. [PMID:15664853]

12. Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R, Han EK, Li T, Stoll VS, Powlas JA et al.. (2005) Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol. Cancer Ther., 4 (6): 977-86. [PMID:15956255]

13. Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang S, Du-Cuny L, Herbst R et al.. (2010) Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol. Cancer Ther., 9 (3): 706-17. [PMID:20197390]

14. 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]

15. Yan L. Abstract #DDT01-1: MK-2206: A potent oral allosteric AKT inhibitor. Accessed on 18/11/2014. Modified on 18/11/2014. AACR Meeting Abstracts Online; http://aacrmeetingabstracts.org, http://www.aacrmeetingabstracts.org/cgi/content/meeting_abstract/2009/2_Annual_Meeting/DDT01-1?maxtoshow=&hits=10&RESULTFORMAT=1&title=MK-2206&andorexacttitle=and&andorexacttitleabs=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&fdate=1/1/2008&tdate=12/31/2010&resourcetype=HWCIT

16. Yan L. (2009) MK-2206: a potent oral allosteric AKT inhibitor.[Abstract]. AACR Annual Meeting 2009,: Abstract Number: DDT01-1.

17. Yang J, Cron P, Thompson V, Good VM, Hess D, Hemmings BA, Barford D. (2002) Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell, 9 (6): 1227-40. [PMID:12086620]

How to cite this page

Akt (Protein kinase B, PKB) family: AKT serine/threonine kinase 2. Last modified on 25/07/2019. Accessed on 23/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1480.