Target Information

Target General Infomation
Target ID
T67619
Former ID
TTDI00350
Target Name
RAC serine/threonine-protein kinase
Gene Name
AKT1
Synonyms
PKB; PKB alpha; Protein kinase B; Protein kinase B alpha; Proto-oncogene c-Akt; RAC-PK-alpha; RAC-alpha serine/threonine-protein kinase; AKT1
Target Type
Clinical Trial
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
Hematologic malignancies [ICD9: 200-209; ICD10: C81-C86]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Leukemia [ICD9: 208.9; ICD10: C90-C95]
Myocardial reperfusion injury [ICD10: T86.4]
Pancreatic cancer [ICD9: 140-199, 140-229, 157, 210-229; ICD10: C25]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.
BioChemical Class
Kinase
Target Validation
T46105
UniProt ID
P31749
EC Number
EC 2.7.11.1
Sequence
MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF
RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI
LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS
RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI
KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL
ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK
LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
Structure
1H10; 1UNP; 1UNQ; 1UNR; 2UVM; 2UZR; 2UZS; 3CQU; 3CQW; 3MV5; 3MVH; 3O96; 3OCB; 3OW4; 3QKK; 3QKL; 3QKM; 4EJN; 4EKK; 4EKL; 4GV1
Drugs and Mode of Action
Drug(s) CI-1033 Drug Info Phase 2 Lymphoma [525738], [541018]
CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
CMX-2043 Drug Info Phase 2 Myocardial reperfusion injury [524699]
GSK2110183 Drug Info Phase 2 Leukemia [523646]
RG7440 Drug Info Phase 2 Solid tumours [549061]
RX-0201 Drug Info Phase 2 Solid tumours [522885]
Trametinib + 2141795 Drug Info Phase 2 Cancer [524432]
Triciribine prodrug Drug Info Phase 1/2 Cancer [524064]
BMS-754807 Drug Info Phase 1 Discovery agent [522661], [542868]
GDC-0068 Drug Info Phase 1 Solid tumours [542812], [550794]
Inhibitor (Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-one Drug Info [528864]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Drug Info [527308]
4,5,6-trihydroxy-3-methylphthalide Drug Info [527356]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Drug Info [528490]
A-443654 Drug Info [528858]
A-674563 Drug Info [531679]
Akt inhibitor VIII Drug Info [527396]
AKT inhibitors [PMCID:PMC3086120] Drug Info [543423]
AKT protein kinase inhibitors Drug Info [543423]
ALM-301 Drug Info [543423]
ARRY-886 Drug Info [543423]
BISINDOLYLMALEIMIDE IX Drug Info [525872]
BMS-536924 Drug Info [527711]
BMS-754807 Drug Info [530403]
BX-517 Drug Info [528864]
CI-1033 Drug Info [536474]
CI-1040 Drug Info [525872]
compound 1 Drug Info [530572]
GDC-0068 Drug Info [550794]
GF-109203 Drug Info [525872]
Inositol 1,3,4,5-Tetrakisphosphate Drug Info [551393]
KN-62 Drug Info [525872]
Lactoquinomycin Drug Info [537458]
LD-101 Drug Info [543423]
MYRIOCIN Drug Info [529608]
RO-316233 Drug Info [525872]
RX-0201 Drug Info [550543]
SB-747651A Drug Info [529701]
STAUROSPORINONE Drug Info [525872]
Triciribine prodrug Drug Info [543423]
VLI-27 Drug Info [543423]
ZARAGOZIC ACIDS A Drug Info [529608]
Modulator CMX-2043 Drug Info [532747]
GSK2110183 Drug Info [543423]
RG7440 Drug Info [550800]
Trametinib + 2141795 Drug Info [543423]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway MAPK signaling pathway
ErbB signaling pathway
Ras signaling pathway
Rap1 signaling pathway
cGMP-PKG signaling pathway
cAMP signaling pathway
Chemokine signaling pathway
HIF-1 signaling pathway
FoxO signaling pathway
Sphingolipid signaling pathway
mTOR signaling pathway
PI3K-Akt signaling pathway
AMPK signaling pathway
Apoptosis
Adrenergic signaling in cardiomyocytes
VEGF signaling pathway
Osteoclast differentiation
Focal adhesion
Tight junction
Signaling pathways regulating pluripotency of stem cells
Platelet activation
Toll-like receptor signaling pathway
Jak-STAT signaling pathway
T cell receptor signaling pathway
B cell receptor signaling pathway
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
TNF signaling pathway
Neurotrophin signaling pathway
Cholinergic synapse
Dopaminergic synapse
Insulin signaling pathway
Progesterone-mediated oocyte maturation
Estrogen signaling pathway
Prolactin signaling pathway
Thyroid hormone signaling pathway
Adipocytokine signaling pathway
Glucagon signaling pathway
Regulation of lipolysis in adipocytes
Non-alcoholic fatty liver disease (NAFLD)
Carbohydrate digestion and absorption
Chagas disease (American trypanosomiasis)
Toxoplasmosis
Tuberculosis
Hepatitis C
Hepatitis B
Measles
Influenza A
HTLV-I infection
Epstein-Barr virus infection
Pathways in cancer
Proteoglycans in cancer
Colorectal cancer
Renal cell carcinoma
Pancreatic cancer
Endometrial cancer
Glioma
Prostate cancer
Melanoma
Chronic myeloid leukemia
Acute myeloid leukemia
Small cell lung cancer
Non-small cell lung cancer
Central carbon metabolism in cancer
Choline metabolism in cancer
NetPath Pathway TSH Signaling Pathway
PANTHER Pathway Angiogenesis
Apoptosis signaling pathway
EGF receptor signaling pathway
Endothelin signaling pathway
FGF signaling pathway
Huntington disease
Hypoxia response via HIF activation
Inflammation mediated by chemokine and cytokine signaling pathway
Insulin/IGF pathway-protein kinase B signaling cascade
Interleukin signaling pathway
PI3 kinase pathway
T cell activation
VEGF signaling pathway
p53 pathway
Ras Pathway
p53 pathway by glucose deprivation
p53 pathway feedback loops 2
CCKR signaling map ST
Pathway Interaction Database Regulation of nuclear SMAD2/3 signaling
Fc-epsilon receptor I signaling in mast cells
Endothelins
BCR signaling pathway
LPA receptor mediated events
Insulin Pathway
IL4-mediated signaling events
TCR signaling in na&amp
#xef
ve CD4+ T cells
Plasma membrane estrogen receptor signaling
CD40/CD40L signaling
Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
Signaling events mediated by PTP1B
S1P3 pathway
Coregulation of Androgen receptor activity
Reelin signaling pathway
Integrin-linked kinase signaling
TCR signaling in na&amp
ve CD8+ T cells
Angiopoietin receptor Tie2-mediated signaling
FAS (CD95) signaling pathway
Thromboxane A2 receptor signaling
Regulation of Telomerase
FOXA2 and FOXA3 transcription factor networks
Glucocorticoid receptor regulatory network
mTOR signaling pathway
CXCR4-mediated signaling events
IGF1 pathway
FoxO family signaling
IL2 signaling events mediated by PI3K
Ceramide signaling pathway
p75(NTR)-mediated signaling
E-cadherin signaling in the nascent adherens junction
amb2 Integrin signaling
Integrins in angiogenesis
IFN-gamma pathway
ErbB1 downstream signaling
ErbB2/ErbB3 signaling events
IL6-mediated signaling events
E-cadherin signaling in keratinocytes
Nephrin/Neph1 signaling in the kidney podocyte
Retinoic acid receptors-mediated signaling
IL8- and CXCR2-mediated signaling events
Signaling events mediated by the Hedgehog family
Nongenotropic Androgen signaling
Hedgehog signaling events mediated by Gli proteins
Caspase Cascade in Apoptosis
CXCR3-mediated signaling events
VEGFR1 specific signals
Signaling events mediated by Stem cell factor receptor (c-Kit)
Signaling events mediated by VEGFR1 and VEGFR2
a6b1 and a6b4 Integrin signaling
Aurora A signaling
Insulin-mediated glucose transport
Class I PI3K signaling events mediated by Akt
IL8- and CXCR1-mediated signaling events
HIF-1-alpha transcription factor network
p53 pathway
Trk receptor signaling mediated by PI3K and PLC-gamma
VEGFR3 signaling in lymphatic endothelium
FGF signaling pathway
PathWhiz Pathway Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
Fc Epsilon Receptor I Signaling in Mast Cells
Insulin Signalling
Leucine Stimulation on Insulin Signaling
Reactome Activation of BAD and translocation to mitochondria
GPVI-mediated activation cascade
PIP3 activates AKT signaling
Translocation of GLUT4 to the plasma membrane
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
AKT phosphorylates targets in the cytosol
AKT phosphorylates targets in the nucleus
Negative regulation of the PI3K/AKT network
eNOS activation
AKT-mediated inactivation of FOXO1A
Integrin alphaIIb beta3 signaling
Deactivation of the beta-catenin transactivating complex
CD28 dependent PI3K/Akt signaling
CTLA4 inhibitory signaling
gamma signalling through PI3Kgamma
KSRP (KHSRP) binds and destabilizes mRNA
VEGFR2 mediated vascular permeability
TP53 Regulates Metabolic Genes
Constitutive Signaling by AKT1 E17K in Cancer
WikiPathways Toll-like receptor signaling pathway
DNA Damage Response (only ATM dependent)
TCR Signaling Pathway
Notch Signaling Pathway
EPO Receptor Signaling
IL-2 Signaling Pathway
Insulin Signaling
Endochondral Ossification
EGF/EGFR Signaling Pathway
IL-4 Signaling Pathway
TGF beta Signaling Pathway
IL-6 signaling pathway
Wnt Signaling Pathway Netpath
Copper homeostasis
Extracellular vesicle-mediated signaling in recipient cells
Apoptosis-related network due to altered Notch3 in ovarian cancer
IL-3 Signaling Pathway
Cardiac Hypertrophic Response
Translocation of GLUT4 to the Plasma Membrane
Regulation of mRNA Stability by Proteins that Bind AU-rich Elements
PIP3 activates AKT signaling
Signal Transduction of S1P Receptor
T-Cell Receptor and Co-stimulatory Signaling
Primary Focal Segmental Glomerulosclerosis FSGS
Apoptosis
Alpha 6 Beta 4 signaling pathway
BDNF signaling pathway
Integrated Pancreatic Cancer Pathway
Oncostatin M Signaling Pathway
Corticotropin-releasing hormone
Interleukin-11 Signaling Pathway
AGE/RAGE pathway
TNF alpha Signaling Pathway
B Cell Receptor Signaling Pathway
Prostate Cancer
Signaling Pathways in Glioblastoma
TSLP Signaling Pathway
IL17 signaling pathway
IL-7 Signaling Pathway
Regulation of Microtubule Cytoskeleton
TWEAK Signaling Pathway
FSH signaling pathway
Leptin signaling pathway
TSH signaling pathway
RANKL/RANK Signaling Pathway
Integrated Breast Cancer Pathway
SREBP signalling
Integrated Cancer pathway
IL-1 signaling pathway
Metabolism of nitric oxide
Integrin-mediated Cell Adhesion
TFs Regulate miRNAs related to cardiac hypertrophy
MicroRNAs in cardiomyocyte hypertrophy
Angiogenesis
TOR Signaling
Regulation of toll-like receptor signaling pathway
AMPK Signaling
Androgen receptor signaling pathway
IL-5 Signaling Pathway
References
Ref 521505ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 522661ClinicalTrials.gov (NCT00898716) Multiple Ascending Dose Study of BMS-754807 in Patients With Solid Tumors in Japan. U.S. National Institutes of Health.
Ref 522885ClinicalTrials.gov (NCT01028495) A Safety and Efficacy Study of RX-0201 Plus Gemcitabine in Metastatic Pancreatic Cancer. U.S. National Institutes of Health.
Ref 523646ClinicalTrials.gov (NCT01445587) A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma. U.S. National Institutes of Health.
Ref 524064ClinicalTrials.gov (NCT01690468) Triciribine and Carboplatin in Ovarian Cancer. U.S. National Institutes of Health.
Ref 524432ClinicalTrials.gov (NCT01941927) Trametinib With GSK2141795 in BRAF Wild-type Melanoma. U.S. National Institutes of Health.
Ref 524699ClinicalTrials.gov (NCT02103959) Safety and Efficacy of CMX-2043 for Protection of the Heart and Kidneys in Subjects Undergoing Coronary Angiography. U.S. National Institutes of Health.
Ref 525738Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem. 2000 Apr 6;43(7):1380-97.
Ref 541018(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5675).
Ref 541019(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5676).
Ref 542812(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7887).
Ref 542868(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7952).
Ref 549061Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031868)
Ref 550794Clinical pipeline report, company report or official report of Genentech (2011).
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 527356J Nat Prod. 2004 Dec;67(12):2086-9.A phthalide with in vitro growth inhibitory activity from an oidiodendron strain.
Ref 527396Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4.
Ref 527711J Med Chem. 2005 Sep 8;48(18):5639-43.Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 528858J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25.Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.
Ref 528864Bioorg Med Chem Lett. 2007 Jul 15;17(14):3814-8. Epub 2007 Apr 27.Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity.
Ref 529608Nat Chem Biol. 2008 Sep;4(9):538-47. Epub 2008 Jul 20.Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation.
Ref 529701J Med Chem. 2008 Sep 25;51(18):5663-79.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.
Ref 530403J Med Chem. 2009 Dec 10;52(23):7360-3.Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.
Ref 5305722,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg Med Chem Lett. 2010 Jan 15;20(2):679-83.
Ref 531679Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.
Ref 532747Pre-clinical and Clinical Safety Studies of CMX-2043: a cytoprotective lipoic acid analogue for ischaemia-reperfusion injury. Basic Clin Pharmacol Toxicol. 2014 Nov;115(5):456-64.
Ref 536474A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
Ref 537458The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9.
Ref 543423(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1479).
Ref 550543CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
Ref 550794Clinical pipeline report, company report or official report of Genentech (2011).
Ref 550800Clinical pipeline report, company report or official report of Genentech.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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