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AKT serine/threonine kinase 3

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Target not currently curated in GtoImmuPdb

Target id: 2286

Nomenclature: AKT serine/threonine kinase 3

Abbreviated Name: AKT3

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 - 479 1q43-q44 AKT3 AKT serine/threonine kinase 3
Mouse - 479 1 H4 Akt3 thymoma viral proto-oncogene 3
Rat - 479 13q25 Akt3 AKT serine/threonine kinase 3
Previous and Unofficial Names Click here for help
MPPH | PKB gamma | protein kinase B gamma | PKB2 | PKBG | v-akt murine thymoma viral oncogene homolog 3
Database Links Click here for help
Alphafold Q9Y243 (Hs), Q9WUA6 (Mm), Q63484 (Rn)
BRENDA 2.7.11.1
CATH/Gene3D 2.30.29.30
ChEMBL Target CHEMBL4816 (Hs)
Ensembl Gene ENSG00000117020 (Hs), ENSMUSG00000019699 (Mm), ENSRNOG00000021497 (Rn)
Entrez Gene 10000 (Hs), 23797 (Mm), 29414 (Rn)
Human Protein Atlas ENSG00000117020 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:10000 (Hs), mmu:23797 (Mm), rno:29414 (Rn)
OMIM 611223 (Hs)
Orphanet ORPHA299660 (Hs)
Pharos Q9Y243 (Hs)
RefSeq Nucleotide NM_005465 (Hs), NM_011785 (Mm), NM_031575 (Rn)
RefSeq Protein NP_005456 (Hs), NP_035915 (Mm), NP_113763 (Rn)
UniProtKB Q9Y243 (Hs), Q9WUA6 (Mm), Q63484 (Rn)
Wikipedia AKT3 (Hs)
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

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 12
⤷ pKi ~9.8 (Ki ~1.6x10-10 M) [12]
uprosertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.8 pKi 6
⤷ pKi 8.8 (Ki 1.5x10-9 M) [6]
afuresertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.6 pKi 6
⤷ pKi 8.6 (Ki 2.6x10-9 M) [6]
NTQ1062 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 10.0 pIC50 13
⤷ pIC50 10.0 (IC50 1x10-10 M) [13]
compound 1 [PMID: 20005102] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 10
⤷ pIC50 9.0 (IC50 1x10-9 M) [10]
rupitasertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 14
⤷ pIC50 9.0 (IC50 1x10-9 M) [14]
compound E22 [PMID: 31298542] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.8 pIC50 5
⤷ pIC50 8.8 (IC50 1.7x10-9 M) [5]
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 8.1 pIC50 1
⤷ pIC50 8.1 (IC50 8x10-9 M) [1]
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 8.1 pIC50 3
⤷ pIC50 8.1 (IC50 8x10-9 M) [3]
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 8.1 pIC50 8
⤷ pIC50 8.1 (IC50 9x10-9 M) [8]
miransertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 19
⤷ pIC50 8.0 (IC50 9.9x10-9 M) [19]
pifusertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 15
⤷ pIC50 7.4 (IC50 4.4x10-8 M) [15]
MS15 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 pIC50 19
⤷ pIC50 6.3 (IC50 5.44x10-7 M) [19]
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 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pIC50 9
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [9]
MK-2206 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Negative 7.2 pIC50 17-18
⤷ pIC50 7.2 (IC50 6.5x10-8 M) [17-18]
Akt inhibitor VIII Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Negative 5.7 pIC50 11
⤷ pIC50 5.7 (IC50 2.119x10-6 M) [11]
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: 4,16
Key to terms and symbols Click column headers to sort
Target used in screen: AKT3
Ligand Sp. Type Action Value Parameter
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
enzastaurin Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.8 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.6 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
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: 2,7
Key to terms and symbols Click column headers to sort
Target used in screen: PKBγ/AKT3
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 3.0 0.0 0.5
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 27.1 96.0 84.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 27.3 11.0 3.0
GF109203X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 31.5 30.0 7.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 55.1 22.0 14.0
Ro-32-0432 Small molecule or natural product Hs Inhibitor Inhibition 56.3
Gö 6983 Small molecule or natural product Hs Inhibitor Inhibition 63.7 30.0 9.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 69.0 31.0 4.0
PKCbeta inhibitor Small molecule or natural product Hs Inhibitor Inhibition 71.0 50.0 15.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 71.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Hemimegalencephaly
Orphanet: ORPHA99802
Disease:  Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2; MPPH2
Synonyms: Megalencephaly - polymicrogyria - postaxial polydactyly - hydrocephalus [Orphanet: ORPHA83473]
OMIM: 615937
Orphanet: ORPHA83473

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. 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]

14. 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]

15. 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]

16. 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]

17. 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

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

19. 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 3. Last modified on 07/06/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2286.