Target Information

Target General Information

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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

Breast cancer [ICD-11: 2C60-2C6Y]

Colorectal cancer [ICD-11: 2B91]

Lymphoma [ICD-11: 2A80-2A86]

Rectum cancer [ICD-11: 2B92]

Acute myeloid leukaemia [ICD-11: 2A60]

Malignant haematopoietic neoplasm [ICD-11: 2B33]

Multiple myeloma [ICD-11: 2A83]

Overgrowth syndrome [ICD-11: LD2C]

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

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Clinical Trial Drug(s)

[+] 14 Clinical Trial Drugs

AZD5363

Drug Info

Phase 2

Solid tumour/cancer

[2], [3]

GSK2141795

Drug Info

Phase 2

Lymphoma

[4], [5]

MK-2206

Drug Info

Phase 2

Rectal adenocarcinoma

[6], [7]

Afuresertib

Drug Info

Phase 1

Multiple myeloma

[8], [9]

ARQ 092

Drug Info

Phase 1

Solid tumour/cancer

[10]

BAY1125976

Drug Info

Phase 1

Solid tumour/cancer

[11]

GSK690693

Drug Info

Phase 1

Haematological malignancy

[12], [13]

LY2780301

Drug Info

Phase 1

Solid tumour/cancer

[14]

LYS-6KAKT1

Drug Info

Phase 1

Solid tumour/cancer

[15]

M2698

Drug Info

Phase 1

Solid tumour/cancer

[16]

MSC2363318A

Drug Info

Phase 1

Solid tumour/cancer

[17]

SR13668

Drug Info

Phase 1

Solid tumour/cancer

[18]

TCN-P

Drug Info

Phase 1

Acute myeloid leukaemia

[19]

XL418

Drug Info

Phase 1

Solid tumour/cancer

[20]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 13 Modulator drugs

AZD5363

Drug Info

[21]

GSK2141795

Drug Info

[1], [22]

MK-2206

Drug Info

[23]

Afuresertib

Drug Info

[21]

ARQ 092

Drug Info

[24]

BAY1125976

Drug Info

[24]

GSK690693

Drug Info

[25], [26]

LY2780301

Drug Info

[27]

LYS-6KAKT1

Drug Info

[28]

MSC2363318A

Drug Info

[17]

SR13668

Drug Info

[29], [30]

TCN-P

Drug Info

[31]

XL418

Drug Info

[32]

Inhibitor

[+] 4 Inhibitor drugs

M2698

Drug Info

[16]

Akt inhibitor VIII

Drug Info

[33]

ISC-4

Drug Info

[34]

PMID20005102C1

Drug Info

[35]

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways		Top
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

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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

REF 5

ClinicalTrials.gov (NCT01958112) GSK1120212+GSK2141795 for Cervical Cancer. U.S. National Institutes of Health.

REF 6

REF 7

ClinicalTrials.gov (NCT01249105) MK-2206 for Recurrent Malignant Glioma. U.S. National Institutes of Health.

REF 8

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

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

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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