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AKT serine/threonine kinase 1

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Target id: 1479

Nomenclature: AKT serine/threonine kinase 1

Abbreviated Name: Akt1

Family: Akt (Protein kinase B, PKB) family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 480 14q32.33 AKT1 AKT serine/threonine kinase 1
Mouse - 480 12 61.2 cM Akt1 thymoma viral proto-oncogene 1
Rat - 480 6q32 Akt1 AKT serine/threonine kinase 1
Previous and Unofficial Names Click here for help
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 | v-akt murine thymoma viral oncogene homolog 1
Database Links Click here for help
Alphafold P31749 (Hs), P31750 (Mm), P47196 (Rn)
BRENDA 2.7.11.11
CATH/Gene3D 2.30.29.30
ChEMBL Target CHEMBL4282 (Hs), CHEMBL5859 (Mm), CHEMBL1075215 (Rn)
Ensembl Gene ENSG00000142208 (Hs), ENSMUSG00000001729 (Mm), ENSRNOG00000028629 (Rn)
Entrez Gene 207 (Hs), 11651 (Mm), 24185 (Rn)
Human Protein Atlas ENSG00000142208 (Hs)
KEGG Enzyme 2.7.11.11
KEGG Gene hsa:207 (Hs), mmu:11651 (Mm), rno:24185 (Rn)
OMIM 164730 (Hs)
Orphanet ORPHA281472 (Hs)
Pharos P31749 (Hs)
RefSeq Nucleotide NM_001014431 (Hs), NM_009652 (Mm), NM_033230 (Rn)
RefSeq Protein NP_001014431 (Hs), NP_033782 (Mm), NP_001159366 (Mm), NP_150233 (Rn)
SynPHARM 80200 (in complex with AZD5363)
80753 (in complex with ipatasertib)
UniProtKB P31749 (Hs), P31750 (Mm), P47196 (Rn)
Wikipedia AKT1 (Hs)
Selected 3D Structures Click here for help
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:  18
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of allosteric inhibitor, ARQ 092, in complex with autoinhibited form of AKT1
PDB Id:  5KCV
Ligand:  miransertib
Resolution:  2.7Å
Species:  Human
References:  12
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
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 8.7 pKd 7
⤷ pKd 8.7 (Kd 2.2x10-9 M) [7]
A-674563 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.1 pKd 7
⤷ pKd 7.1 (Kd 7.6x10-8 M) [7]
uprosertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 10.2 pKi 9
⤷ pKi 10.2 (Ki 6.6x10-11 M) [9]
afuresertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 10.1 pKi 9
⤷ pKi 10.1 (Ki 8x10-11 M) [9]
A-443654 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.8 pKi 15
⤷ pKi 9.8 (Ki 1.6x10-10 M) [15]
A-674563 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pKi 15
⤷ pKi 8.0 (Ki 1.1x10-8 M) [15]
NTQ1062 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.4 pIC50 16
⤷ pIC50 9.4 (IC50 4x10-10 M) [16]
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 9.0 pIC50 4
⤷ pIC50 9.0 (IC50 1x10-9 M) [4]
compound 1 [PMID: 20005102] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 13
⤷ pIC50 9.0 (IC50 1x10-9 M) [13]
rupitasertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
miransertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.9 pIC50 24
⤷ pIC50 8.9 (IC50 1.3x10-9 M) [24]
compound E22 [PMID: 31298542] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.9 pIC50 8
⤷ pIC50 8.9 (IC50 1.37x10-9 M) [8]
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 8.7 pIC50 11
⤷ pIC50 8.7 (IC50 2x10-9 M) [11]
Hu7691 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 6
⤷ pIC50 8.4 (IC50 4x10-9 M) [6]
pifusertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 19
⤷ pIC50 8.3 (IC50 4.8x10-9 M) [19]
capivasertib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.6 – 8.5 pIC50 1,8
⤷ pIC50 8.5 (IC50 3x10-9 M) [1]
pIC50 7.6 (IC50 2.543x10-8 M) [8]
MS15 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.1 pIC50 24
⤷ pIC50 6.1 (IC50 7.98x10-7 M) [24]
oridonin Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.1 pIC50 20
⤷ pIC50 5.1 (IC50 8.4x10-6 M) [20]
miltefosine Small molecule or natural product Approved drug Immunopharmacology Ligand Hs Inhibition 5.0 pIC50 2
⤷ pIC50 5.0 (IC50 9.6x10-6 M) [2]
Description: Measuring inhibition of AKT1 phosphorylation in A549 human epithelial lung cancer cells.
Inhibitor Comments
Note that A-443654 has similar potency across all three Akt isoforms [15].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MK-2206 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Negative 8.3 pIC50 22-23
⤷ pIC50 8.3 (IC50 5x10-9 M) [22-23]
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 8.3 pIC50 12
⤷ pIC50 8.3 (IC50 5x10-9 M) [12]
BAY1125976 Small molecule or natural product Click here for species-specific activity table Hs Negative 8.3 pIC50 5
⤷ pIC50 8.3 (IC50 5.2x10-9 M) [5]
Description: Biochemical inhibition in a TR-FRET assay using full-length human AKT1 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 7.2 pIC50 14
⤷ pIC50 7.2 (IC50 5.8x10-8 M) [14]
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: 7,21
Key to terms and symbols Click column headers to sort
Target used in screen: AKT1
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 7.7 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0 pKd
ruboxistaurin 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
linifanib Small molecule or natural product Hs Inhibitor Inhibition <5.5 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
gefitinib Small molecule or natural product Approved drug Ligand has a PDB structure 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: 3,10
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 10.5 3.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 41.6 95.0 22.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 63.9 107.0 95.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 79.2 99.0 106.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 79.7 103.0 112.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 81.3 97.0 99.0
Cdk4 inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 83.3 111.0 107.0
bohemine Small molecule or natural product Hs Inhibitor Inhibition 83.4 107.0 110.0
VX-702 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 84.7
K-252a Small molecule or natural product Hs Inhibitor Inhibition 86.2 101.0 37.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Immuno Process:  Inflammation
Clinically-Relevant Mutations and Pathophysiology Click here for help
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 disease [Disease Ontology: DOID:6457]
Cowden syndrome [Orphanet: ORPHA201]
Disease Ontology: DOID:6457
OMIM: 615109
Orphanet: ORPHA201
Disease:  Proteus syndrome
Disease Ontology: DOID:13482
OMIM: 176920
Orphanet: ORPHA744

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. Alam MM, Joh EH, Park H, Kim B, Kim DH, Lee YS. (2013) Synthesis, characterization and Akt phosphorylation inhibitory activity of cyclopentanecarboxylate-substituted alkylphosphocholines. Bioorg Med Chem, 21 (7): 2018-24. [PMID:23415083]

3. 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]

4. 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]

5. 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.

6. Che J, Dai X, Gao J, Sheng H, Zhan W, Lu Y, Li D, Gao Z, Jin Z, Chen B et al.. (2021) Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity. J Med Chem, 64 (16): 12163-12180. [PMID:34375113]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. Ma C, Wu J, Wang L, Ji X, Wu Y, Miao L, Chen D, Zhang L, Wu Y, Feng H et al.. (2022) Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors. J Med Chem, 65 (12): 8144-8168. [PMID:35679512]

17. Machl A, Wilker EW, Tian H, Liu X, Schroeder P, Clark A, Huck BR. (2016) M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier. Am J Cancer Res, 6 (4): 806-18. [PMID:27186432]

18. 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]

19. Mimura N, Hideshima T, Shimomura T, Suzuki R, Ohguchi H, Rizq O, Kikuchi S, Yoshida Y, Cottini F, Jakubikova J et al.. (2014) Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. Cancer Res, 74 (16): 4458-69. [PMID:24934808]

20. Song M, Liu X, Liu K, Zhao R, Huang H, Shi Y, Zhang M, Zhou S, Xie H, Chen H et al.. (2018) Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo. Mol Cancer Ther, 17 (7): 1540-1553. [PMID:29695636]

21. 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]

22. 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

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

24. Yu X, Xu J, Cahuzac KM, Xie L, Shen Y, Chen X, Liu J, Parsons RE, Jin J. (2022) Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells. J Med Chem, 65 (20): 14237-14260. [PMID:36197750]

How to cite this page

Akt (Protein kinase B, PKB) family: AKT serine/threonine kinase 1. Last modified on 11/01/2024. Accessed on 10/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1479.