Target General Infomation
Target ID
T71266 (Former ID: TTDI02016)
Target Name
RAC-gamma serine/threonine-protein kinase (AKT3)
Synonyms
STK-2; RAC-PK-gamma; Protein kinase B gamma; Protein kinase Akt-3; PKBG; PKB gamma
Gene Name
AKT3
Target Type
Clinical trial target
[1]
Disease [+] 9 Target-related Diseases +
1 Breast cancer [ICD-11: 2C60-2C6Y]
2 Colorectal cancer [ICD-11: 2B91]
3 Lymphoma [ICD-11: 2A80-2A86]
4 Rectum cancer [ICD-11: 2B92]
5 Acute myeloid leukaemia [ICD-11: 2A60]
6 Malignant haematopoietic neoplasm [ICD-11: 2B33]
7 Multiple myeloma [ICD-11: 2A83]
8 Overgrowth syndrome [ICD-11: LD2C]
9 Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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 interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.
BioChemical Class
Kinase
UniProt ID
AKT3_HUMAN
EC Number
EC 2.7.11.1
Sequence
MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ
LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS
PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK
KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE
RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA
ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM
EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP
PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE
Drugs and Modes of Action
Clinical Trial Drug(s) [+] 14 Clinical Trial Drugs +
1 AZD5363 Drug Info Phase 2 Solid tumour/cancer [2], [3]
2 GSK2141795 Drug Info Phase 2 Lymphoma [4], [5]
3 MK-2206 Drug Info Phase 2 Rectal adenocarcinoma [6], [7]
4 Afuresertib Drug Info Phase 1 Multiple myeloma [8], [9]
5 ARQ 092 Drug Info Phase 1 Solid tumour/cancer [10]
6 BAY1125976 Drug Info Phase 1 Solid tumour/cancer [11]
7 GSK690693 Drug Info Phase 1 Haematological malignancy [12], [13]
8 LY2780301 Drug Info Phase 1 Solid tumour/cancer [14]
9 LYS-6KAKT1 Drug Info Phase 1 Solid tumour/cancer [15]
10 M2698 Drug Info Phase 1 Solid tumour/cancer [16]
11 MSC2363318A Drug Info Phase 1 Solid tumour/cancer [17]
12 SR13668 Drug Info Phase 1 Solid tumour/cancer [18]
13 TCN-P Drug Info Phase 1 Acute myeloid leukaemia [19]
14 XL418 Drug Info Phase 1 Solid tumour/cancer [20]
Mode of Action [+] 2 Modes of Action +
Modulator [+] 13 Modulator drugs +
1 AZD5363 Drug Info [21]
2 GSK2141795 Drug Info [1], [22]
3 MK-2206 Drug Info [23]
4 Afuresertib Drug Info [21]
5 ARQ 092 Drug Info [24]
6 BAY1125976 Drug Info [24]
7 GSK690693 Drug Info [25], [26]
8 LY2780301 Drug Info [27]
9 LYS-6KAKT1 Drug Info [28]
10 MSC2363318A Drug Info [17]
11 SR13668 Drug Info [29], [30]
12 TCN-P Drug Info [31]
13 XL418 Drug Info [32]
Inhibitor [+] 4 Inhibitor drugs +
1 M2698 Drug Info [16]
2 Akt inhibitor VIII Drug Info [33]
3 ISC-4 Drug Info [34]
4 PMID20005102C1 Drug Info [35]
Target Regulators
Target-regulating microRNAs
Target-interacting Proteins
Target Profiles in Patients
Target Expression
 Profile (TEP)
Drug Resistance
 Mutation (DRM)
Target Affiliated Biological Pathways
KEGG Pathway [+] 65 KEGG Pathways +
1 MAPK signaling pathway
2 ErbB signaling pathway
3 Ras signaling pathway
4 Rap1 signaling pathway
5 cGMP-PKG signaling pathway
6 cAMP signaling pathway
7 Chemokine signaling pathway
8 HIF-1 signaling pathway
9 FoxO signaling pathway
10 Sphingolipid signaling pathway
11 mTOR signaling pathway
12 PI3K-Akt signaling pathway
13 AMPK signaling pathway
14 Apoptosis
15 Adrenergic signaling in cardiomyocytes
16 VEGF signaling pathway
17 Osteoclast differentiation
18 Focal adhesion
19 Tight junction
20 Signaling pathways regulating pluripotency of stem cells
21 Platelet activation
22 Toll-like receptor signaling pathway
23 Jak-STAT signaling pathway
24 T cell receptor signaling pathway
25 B cell receptor signaling pathway
26 Fc epsilon RI signaling pathway
27 Fc gamma R-mediated phagocytosis
28 TNF signaling pathway
29 Neurotrophin signaling pathway
30 Cholinergic synapse
31 Dopaminergic synapse
32 Insulin signaling pathway
33 Progesterone-mediated oocyte maturation
34 Estrogen signaling pathway
35 Prolactin signaling pathway
36 Thyroid hormone signaling pathway
37 Adipocytokine signaling pathway
38 Glucagon signaling pathway
39 Regulation of lipolysis in adipocytes
40 Non-alcoholic fatty liver disease (NAFLD)
41 Carbohydrate digestion and absorption
42 Chagas disease (American trypanosomiasis)
43 Toxoplasmosis
44 Tuberculosis
45 Hepatitis C
46 Hepatitis B
47 Measles
48 Influenza A
49 HTLV-I infection
50 Epstein-Barr virus infection
51 Pathways in cancer
52 Proteoglycans in cancer
53 Colorectal cancer
54 Renal cell carcinoma
55 Pancreatic cancer
56 Endometrial cancer
57 Glioma
58 Prostate cancer
59 Melanoma
60 Chronic myeloid leukemia
61 Acute myeloid leukemia
62 Small cell lung cancer
63 Non-small cell lung cancer
64 Central carbon metabolism in cancer
65 Choline metabolism in cancer
NetPath Pathway [+] 2 NetPath Pathways +
1 TSH Signaling Pathway
2 IL2 Signaling Pathway
Panther Pathway [+] 15 Panther Pathways +
1 Angiogenesis
2 Apoptosis signaling pathway
3 EGF receptor signaling pathway
4 Endothelin signaling pathway
5 FGF signaling pathway
6 Huntington disease
7 Hypoxia response via HIF activation
8 Inflammation mediated by chemokine and cytokine signaling pathway
9 Interleukin signaling pathway
10 PI3 kinase pathway
11 T cell activation
12 p53 pathway
13 Ras Pathway
14 p53 pathway by glucose deprivation
15 p53 pathway feedback loops 2
PID Pathway [+] 2 PID Pathways +
1 S1P3 pathway
2 Class I PI3K signaling events mediated by Akt
References
REF 1 Inhibiting the akt pathway in cancer treatment: three leading candidates. P T. 2011 Apr;36(4):225-7.
REF 2 URL: 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 3 ClinicalTrials.gov (NCT02077569) AKT Inhibitor in Oestrogen Positive Breast Cancer. U.S. National Institutes of Health.
REF 4 URL: 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 5 ClinicalTrials.gov (NCT01958112) GSK1120212+GSK2141795 for Cervical Cancer. U.S. National Institutes of Health.
REF 6 URL: 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 7 ClinicalTrials.gov (NCT01249105) MK-2206 for Recurrent Malignant Glioma. U.S. National Institutes of Health.
REF 8 URL: 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 9 ClinicalTrials.gov (NCT02040480) Bioavailability and Food Effect Study of Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib. U.S. National Institutes of Health.
REF 10 ClinicalTrials.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 11 ClinicalTrials.gov (NCT01915576) Phase I Dose Escalation Study With an Allosteric AKT 1/2 Inhibitor in Patients. U.S. National Institutes of Health.
REF 12 URL: 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 13 ClinicalTrials.gov (NCT00666081) Study to Investigate AKT Inhibitor GSK690693 in Subjects With Relapsed or Refractory Hematologic Malignancies. U.S. National Institutes of Health.
REF 14 ClinicalTrials.gov (NCT01115751) A Study in Patients With Advanced or Metastatic Cancer. U.S. National Institutes of Health.
REF 15 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034531)
REF 16 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 17 ClinicalTrials.gov (NCT01971515) First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies. U.S. National Institutes of Health.
REF 18 ClinicalTrials.gov (NCT00896207) Studying Different Formulations of SR13668 in Healthy Volunteers. U.S. National Institutes of Health.
REF 19 ClinicalTrials.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 20 ClinicalTrials.gov (NCT00460278) Study of XL418 in Adults With Solid Tumors. U.S. National Institutes of Health.
REF 21 The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014 Oct 2;124(14):2190-5.
REF 22 Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014 Jun 30;9(6):e100880.
REF 23 First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.J Clin Oncol.2011 Dec 10;29(35):4688-95.
REF 24 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 25 Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity.Cancer Res.2008 Apr 1;68(7):2366-74.
REF 26 AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines.Blood.2009 Feb 19;113(8):1723-9.
REF 27 A 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 28 DOI: 10.1016/S1359-6349(10)71767-5
REF 29 Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668. Cancer Prev Res (Phila). 2011 Mar;4(3):347-53.
REF 30 Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys. Cancer Chemother Pharmacol. 2010 May;65(6):1109-16.
REF 31 Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT.Invest New Drugs.2011 Dec;29(6):1381-9.
REF 32 Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer
REF 33 Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4.
REF 34 URL: 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 35 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.

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