Target Information

Target General Infomation
Target ID
T71266
Former ID
TTDI02016
Target Name
AKT3 protein kinase
Gene Name
AKT3
Synonyms
PKB gamma; Protein kinase B gamma; RAC-PK-gamma; RAC-gamma serine/threonine-protein kinase; STK-2; AKT3
Target Type
Clinical Trial
Disease Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Colorectal cancer; Lymphoma [ICD9:153, 154, 202.8, 208.9; ICD10: C18-C21, C81-C86]
Colon cancer; Rectal cancer [ICD9: 153, 154; ICD10: C50]
Hematologic malignancies [ICD9: 200-209; ICD10: C81-C86]
Inoperable and unresectable late-stage solid tumors [ICD9: 140-199, 210-229; ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
Multiple myeloma [ICD9: 203; ICD10: C90]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
AKT3 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interferencereduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase- dependent apoptosis.
BioChemical Class
Kinase
UniProt ID
Q9Y243
EC Number
EC 2.7.11.1
Sequence
MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ
LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS
PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK
KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE
RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA
ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM
EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP
PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE
Drugs and Mode of Action
Drug(s) AZD5363 Drug Info Phase 2 Cancer [524662], [542684]
GSK2141795 Drug Info Phase 2 Colorectal cancer; Lymphoma [524462], [542825]
MK-2206 Drug Info Phase 2 Colon cancer; Rectal cancer [523269], [542860]
Afuresertib Drug Info Phase 1 Multiple myeloma [524607], [542816]
ARQ 092 Drug Info Phase 1 Inoperable and unresectable late-stage solid tumors [523692]
BAY1125976 Drug Info Phase 1 Cancer [524391]
GSK690693 Drug Info Phase 1 Hematologic malignancies [468252], [522304]
LY2780301 Drug Info Phase 1 Cancer [523025]
LYS-6KAKT1 Drug Info Phase 1 Cancer [549276]
MSC2363318A Drug Info Phase 1 Solid tumours [524495]
SR13668 Drug Info Phase 1 Cancer [522659]
TCN-P Drug Info Phase 1 Acute myeloid leukemia [521869]
XL418 Drug Info Phase 1 Solid tumours [522010]
Modulator Afuresertib Drug Info [532901]
ARQ 092 Drug Info [1572591]
AZD5363 Drug Info [532901]
BAY1125976 Drug Info [1572591]
GSK2141795 Drug Info [531478], [532865]
GSK690693 Drug Info
LY2780301 Drug Info [533217]
LYS-6KAKT1 Drug Info
MK-2206 Drug Info
MSC2363318A Drug Info [524495]
SR13668 Drug Info [530382], [531379]
TCN-P Drug Info
XL418 Drug Info
Inhibitor Akt inhibitor VIII Drug Info [527396]
compound 1 Drug Info [530572]
ISC-4 Drug Info [543586]
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
IL2 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
Interleukin signaling pathway
PI3 kinase pathway
T cell activation
p53 pathway
Ras Pathway
p53 pathway by glucose deprivation
p53 pathway feedback loops 2
Pathway Interaction Database S1P3 pathway
Class I PI3K signaling events mediated by Akt
References
Ref 468252(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: 5196).
Ref 521869ClinicalTrials.gov (NCT00363454) Phase I Study of Triciribine Phosphate Monohydrate (TCN-PM, VD-0002) in Adult Subjects With Metastatic Cancer. U.S. National Institutes of Health.
Ref 522010ClinicalTrials.gov (NCT00460278) Study of XL418 in Adults With Solid Tumors. U.S. National Institutes of Health.
Ref 522304ClinicalTrials.gov (NCT00666081) Study to Investigate AKT Inhibitor GSK690693 in Subjects With Relapsed or Refractory Hematologic Malignancies. U.S. National Institutes of Health.
Ref 522659ClinicalTrials.gov (NCT00896207) Studying Different Formulations of SR13668 in Healthy Volunteers. U.S. National Institutes of Health.
Ref 523025ClinicalTrials.gov (NCT01115751) A Study in Patients With Advanced or Metastatic Cancer. U.S. National Institutes of Health.
Ref 523269ClinicalTrials.gov (NCT01249105) MK-2206 for Recurrent Malignant Glioma. U.S. National Institutes of Health.
Ref 523692ClinicalTrials.gov (NCT01473095) Phase 1 Dose Escalation Study of ARQ 092 in Adult Subjects With Advanced Solid Tumors and Recurrent Malignant Lymphoma. U.S. National Institutes of Health.
Ref 524391ClinicalTrials.gov (NCT01915576) Phase I Dose Escalation Study With an Allosteric AKT 1/2 Inhibitor in Patients. U.S. National Institutes of Health.
Ref 524462ClinicalTrials.gov (NCT01958112) GSK1120212+GSK2141795 for Cervical Cancer. U.S. National Institutes of Health.
Ref 524495ClinicalTrials.gov (NCT01971515) First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies. U.S. National Institutes of Health.
Ref 524607ClinicalTrials.gov (NCT02040480) Bioavailability and Food Effect Study of Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib. U.S. National Institutes of Health.
Ref 524662ClinicalTrials.gov (NCT02077569) AKT Inhibitor in Oestrogen Positive Breast Cancer. U.S. National Institutes of Health.
Ref 542684(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: 7709).
Ref 542816(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: 7890).
Ref 542825(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: 7902).
Ref 542860(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: 7945).
Ref 549276Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034531)
Ref
Ref 524495ClinicalTrials.gov (NCT01971515) First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies. U.S. National Institutes of Health.
Ref 527396Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4.
Ref 530382Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys. Cancer Chemother Pharmacol. 2010 May;65(6):1109-16.
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 531379Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668. Cancer Prev Res (Phila). 2011 Mar;4(3):347-53.
Ref 531478Inhibiting the akt pathway in cancer treatment: three leading candidates. P T. 2011 Apr;36(4):225-7.
Ref 532865Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014 Jun 30;9(6):e100880.
Ref 532901The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014 Oct 2;124(14):2190-5.
Ref 533217A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer. Invest New Drugs. 2015 Jun;33(3):710-9.
Ref 543586(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: 2286).
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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