Target Information
Target General Infomation | |||||
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Target ID |
T67619
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Former ID |
TTDI00350
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Target Name |
RAC serine/threonine-protein kinase
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Gene Name |
AKT1
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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
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Target Type |
Clinical Trial
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Disease | Cancer [ICD9: 140-229; ICD10: C00-C96] | ||||
Hematologic malignancies [ICD9: 200-209; ICD10: C81-C86] | |||||
Leukemia [ICD9: 208.9; ICD10: C90-C95] | |||||
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86] | |||||
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.
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BioChemical Class |
Kinase
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Target Validation |
T46105
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA |
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Structure |
1H10; 1UNP; 1UNQ; 1UNR; 2UVM; 2UZR; 2UZS; 3CQU; 3CQW; 3MV5; 3MVH; 3O96; 3OCB; 3OW4; 3QKK; 3QKL; 3QKM; 4EJN; 4EKK; 4EKL; 4GV1
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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) | |||||
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& | |||||
#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& | |||||
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 521505 | ClinicalTrials.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 522661 | ClinicalTrials.gov (NCT00898716) Multiple Ascending Dose Study of BMS-754807 in Patients With Solid Tumors in Japan. U.S. National Institutes of Health. | ||||
Ref 522885 | ClinicalTrials.gov (NCT01028495) A Safety and Efficacy Study of RX-0201 Plus Gemcitabine in Metastatic Pancreatic Cancer. U.S. National Institutes of Health. | ||||
Ref 523646 | ClinicalTrials.gov (NCT01445587) A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma. U.S. National Institutes of Health. | ||||
Ref 524064 | ClinicalTrials.gov (NCT01690468) Triciribine and Carboplatin in Ovarian Cancer. U.S. National Institutes of Health. | ||||
Ref 524432 | ClinicalTrials.gov (NCT01941927) Trametinib With GSK2141795 in BRAF Wild-type Melanoma. U.S. National Institutes of Health. | ||||
Ref 524699 | ClinicalTrials.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 525738 | Tyrosine 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 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
Ref 527308 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. | ||||
Ref 527356 | J Nat Prod. 2004 Dec;67(12):2086-9.A phthalide with in vitro growth inhibitory activity from an oidiodendron strain. | ||||
Ref 527396 | Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4. | ||||
Ref 527711 | J 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 528490 | J 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 528858 | J 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 528864 | Bioorg 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 529608 | Nat Chem Biol. 2008 Sep;4(9):538-47. Epub 2008 Jul 20.Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation. | ||||
Ref 529701 | J 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 530403 | J 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 530572 | 2,3,5-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 531679 | Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. | ||||
Ref 532747 | Pre-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 536474 | A 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 537458 | The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9. |
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