Target Information
Target General Infomation | |||||
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Target ID |
T71266
(Former ID: TTDI02016)
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Target Name |
RAC-gamma serine/threonine-protein kinase (AKT3)
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Synonyms |
STK-2; RAC-PK-gamma; Protein kinase B gamma; Protein kinase Akt-3; PKBG; PKB gamma
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Gene Name |
AKT3
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Target Type |
Clinical trial target
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[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.
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BioChemical Class |
Kinase
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ
LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE |
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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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