v-akt murine thymoma viral oncogene homolog 1

Target id: 1479

Nomenclature: v-akt murine thymoma viral oncogene homolog 1

Abbreviated Name: Akt1

Family: Akt (Protein kinase B)

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 - 480 14q32.32-q32.33 AKT1 v-akt murine thymoma viral oncogene homolog 1
Mouse - 480 12 F1-2 Akt1 thymoma viral proto-oncogene 1
Rat - 480 6q32 Akt1 v-akt murine thymoma viral oncogene homolog 1
Previous and Unofficial Names
AKT
PRKBA
AKT1 kinase
PKB alpha
protein kinase B alpha
RAC protein kinase alpha RAC-PK alpha
RAC-alpha serine/threonine-protein kinase
RAC-PK-alpha
PKB/Akt
Database Links
BRENDA
Ensembl Gene
Entrez Gene
ExplorEnz
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Enzyme
KEGG Gene
NeXtProt
OMIM
Orphanet
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  PKB alpha in complex with AZD5363
PDB Id:  4GV1
Resolution:  1.49Å
Species:  Human
References:  1
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the pleckstrin homology domain of PKB alpha
PDB Id:  1UNP
Resolution:  1.65Å
Species:  Human
References:  11
Enzyme Reaction
EC Number: 2.7.11.11
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
GSK690693 Hs Inhibition 8.66 pKd 4
pKd 8.66 (Kd 2.2x10-9 M) [4]
A-674563 Hs Inhibition 7.12 pKd 4
pKd 7.12 (Kd 7.6x10-8 M) [4]
uprosertib Hs Inhibition 10.18 pKi 5
pKi 10.18 (Ki 6.6x10-11 M) [5]
afuresertib Hs Inhibition 10.1 pKi 5
pKi 10.1 (Ki 8x10-11 M) [5]
A-443654 Hs Inhibition 9.8 pKi 10
pKi 9.8 (Ki 1.6x10-10 M) [10]
A-674563 Hs Inhibition 7.96 pKi 10
pKi 7.96 (Ki 1.1x10-8 M) [10]
ipatasertib Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
compound 1 [PMID 20005102] Hs Inhibition 9.0 pIC50 8
pIC50 9.0 (IC50 1x10-9 M) [8]
GSK690693 Hs Inhibition 8.7 pIC50 7
pIC50 8.7 (IC50 2x10-9 M) [7]
AZD5363 Hs Inhibition 8.52 pIC50 1
pIC50 8.52 (IC50 3x10-9 M) [1]
MK-2206 Hs Inhibition 8.3 pIC50 13-14
pIC50 8.3 (IC50 5x10-9 M) [13-14]
Akt inhibitor VIII Hs Inhibition 7.24 pIC50 9
pIC50 7.24 (IC50 5.8x10-8 M) [9]
Inhibitor Comments
Note that A-443654 has similar potency across all three Akt isoforms [10].
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: 4,12

Key to terms and symbols Click column headers to sort
Target used in screen: AKT1
Ligand Sp. Type Action Affinity Units
GSK690693 Hs Inhibitor Inhibition 8.66 pKd
staurosporine Hs Inhibitor Inhibition 7.7 pKd
A-674563 Hs Inhibitor Inhibition 7.12 pKd
midostaurin Hs Inhibitor Inhibition 6.02 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.52 pKd
SB203580 Hs Inhibitor Inhibition <5.52 pKd
erlotinib Hs Inhibitor Inhibition <5.52 pKd
linifanib Hs Inhibitor Inhibition <5.52 pKd
masitinib Hs Inhibitor Inhibition <5.52 pKd
gefitinib Hs Inhibitor Inhibition <5.52 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: 2,6

Key to terms and symbols Click column headers to sort
Target used in screen: PKBα/AKT1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 7.5 10.5 3.0
H-89 Hs Inhibitor Inhibition 41.6 95.0 22.0
SB 218078 Hs Inhibitor Inhibition 63.9 107.0 95.0
PKR inhibitor Hs Inhibitor Inhibition 79.2 99.0 106.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 79.7 103.0 112.0
midostaurin Hs Inhibitor Inhibition 81.3 97.0 99.0
Cdk4 inhibitor III Hs Inhibitor Inhibition 83.3 111.0 107.0
bohemine Hs Inhibitor Inhibition 83.4 107.0 110.0
VX-702 Hs Inhibitor Inhibition 84.7
Y27632 Hs Inhibitor Inhibition 86.2 88.0 76.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
Disease:  Colorectal cancer
Disease Ontology: DOID:9256
OMIM: 114500
Disease:  Cowden syndrome 6; CWS6
Synonyms: Cowden syndrome [Orphanet: ORPHA201]
OMIM: 615109
Orphanet: ORPHA201
Disease:  Proteus syndrome
Disease Ontology: DOID:13482
OMIM: 176920
Orphanet: ORPHA744

References

Show »

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. 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 ONE9 (6): e100880. [PMID:24978597]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DM. (2003) Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem. J.375 (Pt 3): 531-8. [PMID:12964941]

12. 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]

13. 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

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

How to cite this page

Akt (Protein kinase B): v-akt murine thymoma viral oncogene homolog 1. Last modified on 24/02/2015. Accessed on 04/07/2015. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1479.