Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTAZ05C)

• DTT 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
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: AKT3_HUMAN
• TTD ID: T71266
• EC Number: EC 2.7.11.1
• Sequence:
  MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ
  LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS
  PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK
  KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE
  RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA
  ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM
  EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP
  PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE
• 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Apoptosis (hsa04210)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  VEGF signaling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Tight junction (hsa04530)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  Toll-like receptor signaling pathway (hsa04620)
  Jak-STAT signaling pathway (hsa04630)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  TNF signaling pathway (hsa04668)
  Neurotrophin signaling pathway (hsa04722)
  Cholinergic synapse (hsa04725)
  Dopaminergic synapse (hsa04728)
  Insulin signaling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Prolactin signaling pathway (hsa04917)
  Thyroid hormone signaling pathway (hsa04919)
  Adipocytokine signaling pathway (hsa04920)
  Glucagon signaling pathway (hsa04922)
  Regulation of lipolysis in adipocytes (hsa04923)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Carbohydrate digestion and absorption (hsa04973)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Colorectal cancer (hsa05210)
  Renal cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Downregulation of ERBB2 (R-HSA-1358803)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)
  AKT phosphorylates targets in the nucleus (R-HSA-198693)
  Negative regulation of the PI3K/AKT network (R-HSA-199418)
  AKT-mediated inactivation of FOXO1A (R-HSA-211163)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CTLA4 inhibitory signaling (R-HSA-389513)
  G beta (R-HSA-392451)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  Regulation of TP53 Activity through Association with Co-factors (R-HSA-6804759)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  Cyclin A (R-HSA-69656)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  RUNX2 regulates genes involved in cell migration (R-HSA-8941332)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  FLT3 Signaling (R-HSA-9607240)
  Regulation of localization of FOXO transcription factors (R-HSA-9614399)
  Estrogen-dependent nuclear events downstream of ESR-membrane signaling (R-HSA-9634638)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  SARS-CoV-2 targets host intracellular signalling and regulatory pathways (R-HSA-9755779)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Capivasertib	DM9SKW8	Breast cancer	2C60-2C65	Approved	[2]

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ARQ 092	DM5WK0J	Proteus syndrome	LD2C	Phase 2	[3]
GSK2141795	DMSHE70	Colorectal cancer	2B91.Z	Phase 2	[1]
MK-2206	DMT1OZ6	Rectal adenocarcinoma	2B92	Phase 2	[4]
BAY1125976	DMTB4R8	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
GSK690693	DMRBVHE	Haematological malignancy	2B33.Y	Phase 1	[5]
LY2780301	DM93AJW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
LYS-6KAKT1	DMLXGAI	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
M2698	DM3PVBJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
SR13668	DMO5760	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
TCN-P	DMV0AH8	Acute myeloid leukaemia	2A60	Phase 1	[10]
XL418	DME0F5W	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Akt inhibitor VIII	DMDVIT1	Discovery agent	N.A.	Investigative	[12]
ISC-4	DMH6YVD	Solid tumour/cancer	2A00-2F9Z	Investigative	[13]
PMID20005102C1	DMMESBW	Discovery agent	N.A.	Investigative	[14]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	6.79E-01	-0.02	-0.08
Multiple myeloma	2C82	Bone marrow	4.52E-03	-0.33	-1.36
Rectal cancer	2C82	Rectal colon tissue	1.12E-01	0.18	1.05
Colon cancer	2C82	Colon tissue	1.34E-02	1.35E-02	0.06

References

• [1] Inhibiting the akt pathway in cancer treatment: three leading candidates. P T. 2011 Apr;36(4):225-7.
• [2] The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014 Oct 2;124(14):2190-5.
• [3] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [4] 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.
• [5] Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity.Cancer Res.2008 Apr 1;68(7):2366-74.
• [6] 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.
• [7] DOI: 10.1016/S1359-6349(10)71767-5
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668. Cancer Prev Res (Phila). 2011 Mar;4(3):347-53.
• [10] 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.
• [11] Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer
• [12] Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4.
• [13] 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).
• [14] 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.