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AKT serine/threonine kinase 2

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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

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 481 19q13.2 AKT2 AKT serine/threonine kinase 2
Mouse - 481 7 15.94 cM Akt2 thymoma viral proto-oncogene 2
Rat - 481 1q21 Akt2 AKT serine/threonine kinase 2
Previous and Unofficial Names Click here for help
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 Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  STRUCTURE OF PROTEIN KINASE B UNPHOSPHORYLATED
PDB Id:  1GZO
Resolution:  2.75Å
Species:  Human
References:  18
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:  9
Enzyme Reaction Click here for help
EC Number: 2.7.11.11

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
A-443654 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition ~9.8 pKi 13
pKi ~9.8 (Ki ~1.6x10-10 M) [13]
uprosertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.9 pKi 7
pKi 8.9 (Ki 1.4x10-9 M) [7]
afuresertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.7 pKi 7
pKi 8.7 (Ki 2x10-9 M) [7]
PHT-427 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 5.6 pKi 14
pKi 5.6 (Ki 2.67x10-6 M) [14]
Description: Assay using purified recombinant pleckstrin homology domain of human Akt2
compound E22 [PMID: 31298542] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.9 pIC50 6
pIC50 8.9 (IC50 1.2x10-9 M) [6]
capivasertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 1
pIC50 8.1 (IC50 8x10-9 M) [1]
compound 1 [PMID: 20005102] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.9 pIC50 11
pIC50 7.9 (IC50 1.2x10-8 M) [11]
GSK690693 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.9 pIC50 9
pIC50 7.9 (IC50 1.3x10-8 M) [9]
ipatasertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure 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 [13].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
miransertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.4 pIC50 10
pIC50 8.4 (IC50 4.5x10-9 M) [10]
MK-2206 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Negative 7.9 pIC50 16-17
pIC50 7.9 (IC50 1.2x10-8 M) [16-17]
BAY1125976 Small molecule or natural product Click here for species-specific activity table Hs Negative 7.7 pIC50 4
pIC50 7.7 (IC50 1.8x10-8 M) [4]
Description: Biochemical inhibition in a TR-FRET assay using full-length human AKT2 and biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG as substrate.
Akt inhibitor VIII Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Negative 6.7 pIC50 12
pIC50 6.7 (IC50 2.1x10-7 M) [12]
DiscoveRx KINOMEscan® screen Click here for help
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: 5,15

Key to terms and symbols Click column headers to sort
Target used in screen: AKT2
Ligand Sp. Type Action Value Parameter
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.7 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.1 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 5.7 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 5.6 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.5 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
linifanib Small molecule or natural product 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 Click here for help
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: 2,8

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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.5 5.0 1.5
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 48.5 101.0 92.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 55.8 133.0 44.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 75.4 86.0 36.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 77.2 80.0 46.0
TGF-beta RI inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 80.1 115.0 95.0
AG1478 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 84.1 128.0 93.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 84.2 67.0 22.0
AG 1296 Small molecule or natural product Hs Inhibitor Inhibition 86.7 111.0 83.0
SU11652 Small molecule or natural product Ligand has a PDB structure 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 Click here for help
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. Bärfacker L, Scott W, Hägebarth A, Ince S, Rehwinkel H, Politz O, Neuhaus R, Briem H, Bömer U. (2012) Imidazopyridazines as Akt kinase inhibitors. Patent number: WO2012136776A1. Assignee: Bayer Pharma AG. Priority date: 07/04/2011. Publication date: 11/10/2012.

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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

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

18. 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 02/06/2020. Accessed on 30/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1480.