AKT serine/threonine kinase 3 | Akt (Protein kinase B, PKB) family | IUPHAR/BPS Guide to PHARMACOLOGY

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AKT serine/threonine kinase 3

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

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 - 479 1q44 AKT3 AKT serine/threonine kinase 3
Mouse - 479 1 H4-H6 Akt3 thymoma viral proto-oncogene 3
Rat - 479 13q24-q26 Akt3 AKT serine/threonine kinase 3
Previous and Unofficial Names
MPPH | PKB gamma | protein kinase B gamma | PKB2 | PKBG | v-akt murine thymoma viral oncogene homolog 3
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.11.1

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 11
pKi ~9.8 (Ki ~1.6x10-10 M) [11]
uprosertib Hs Inhibition 8.8 pKi 5
pKi 8.8 (Ki 1.5x10-9 M) [5]
afuresertib Hs Inhibition 8.6 pKi 5
pKi 8.6 (Ki 2.6x10-9 M) [5]
compound 1 [PMID: 20005102] Hs Inhibition 9.0 pIC50 9
pIC50 9.0 (IC50 1x10-9 M) [9]
capivasertib Hs Inhibition 8.1 pIC50 1
pIC50 8.1 (IC50 8x10-9 M) [1]
ipatasertib Hs Inhibition 8.1 pIC50 3
pIC50 8.1 (IC50 8x10-9 M) [3]
GSK690693 Hs Inhibition 8.1 pIC50 7
pIC50 8.1 (IC50 9x10-9 M) [7]
Inhibitor Comments
Note that A-443654 has similar potency across all three Akt isoforms [11].
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 7.8 pIC50 8
pIC50 7.8 (IC50 1.6x10-8 M) [8]
MK-2206 Hs Negative 7.2 pIC50 13-14
pIC50 7.2 (IC50 6.5x10-8 M) [13-14]
Akt inhibitor VIII Hs Negative 5.7 pIC50 10
pIC50 5.7 (IC50 2.119x10-6 M) [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: AKT3
Ligand Sp. Type Action Value Parameter
GSK690693 Hs Inhibitor Inhibition 8.5 pKd
staurosporine Hs Inhibitor Inhibition 6.8 pKd
A-674563 Hs Inhibitor Inhibition 6.7 pKd
enzastaurin Hs Inhibitor Inhibition 6.0 pKd
ruboxistaurin Hs Inhibitor Inhibition 5.8 pKd
PP-242 Hs Inhibitor Inhibition 5.6 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
linifanib Hs Inhibitor Inhibition <5.5 pKd
masitinib 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: 2,6

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 Hs Inhibitor Inhibition 3.0 0.0 0.5
SB 218078 Hs Inhibitor Inhibition 27.1 96.0 84.0
K-252a Hs Inhibitor Inhibition 27.3 11.0 3.0
GF109203X Hs Inhibitor Inhibition 31.5 30.0 7.0
midostaurin Hs Inhibitor Inhibition 55.1 22.0 14.0
Ro-32-0432 Hs Inhibitor Inhibition 56.3
Gö 6983 Hs Inhibitor Inhibition 63.7 30.0 9.0
H-89 Hs Inhibitor Inhibition 69.0 31.0 4.0
PKCbeta inhibitor Hs Inhibitor Inhibition 71.0 50.0 15.0
sunitinib Hs Inhibitor Inhibition 71.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
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. 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]

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. 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]

9. 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]

10. 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]

11. 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]

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, PKB) family: AKT serine/threonine kinase 3. Last modified on 24/01/2017. Accessed on 20/06/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2286.