Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: RAC-alpha serine/threonine-protein kinase (AKT1)
• Synonyms: RAC-PK-alpha; RAC; Proto-oncogene c-Akt; Protein kinase B alpha; PKB alpha
• Gene Name: AKT1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: AKT1_HUMAN
• TTD ID: T67619
• EC Number: EC 2.7.11.1
• Sequence:
  MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
  QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF
  RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI
  LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS
  RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI
  KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL
  ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK
  LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
• Function: AKT1 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. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53.
• 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:
  GPVI-mediated activation cascade (R-HSA-114604)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Translocation of GLUT4 to the plasma membrane (R-HSA-1445148)
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  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)
  eNOS activation (R-HSA-203615)
  AKT-mediated inactivation of FOXO1A (R-HSA-211163)
  Integrin alphaIIb beta3 signaling (R-HSA-354192)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CTLA4 inhibitory signaling (R-HSA-389513)
  G beta (R-HSA-392451)
  KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  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]

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Enzastaurin	DM5H0R9	Diffuse large B-cell lymphoma	2A81	Phase 3	[2]
GDC-0068	DMWBZJD	Breast cancer	2C60-2C65	Phase 3	[2]
ARQ 092	DM5WK0J	Proteus syndrome	LD2C	Phase 2	[3]
CI-1033	DMSI8N3	Lymphoma	2A80-2A86	Phase 2	[4]
CMX-2043	DMPSCVY	Cardiac disease	BA00-BE2Z	Phase 2	[5]
GSK2110183	DMZHB37	leukaemia	2A60-2B33	Phase 2	[6]
PTX-200	DM0ZIT2	Breast cancer	2C60-2C65	Phase 2	[2]
RX-0201	DMTBAV3	Pancreatic cancer	2C10	Phase 2	[7]
Triciribine prodrug	DMBN1XS	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[6]
ARQ 751	DM7MWX0	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
BMS-754807	DMPK32V	N. A.	N. A.	Phase 1	[8]
M2698	DM3PVBJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID28460551-Compound-6	DMT7U1O	N. A.	N. A.	Patented	[9]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Squalestatin 1	DM4JZPT	Arteriosclerosis	BD40	Terminated	[10]

24 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-one	DM27WDP	Discovery agent	N.A.	Investigative	[11]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[12]
4,5,6-trihydroxy-3-methylphthalide	DMQFTJ7	Discovery agent	N.A.	Investigative	[13]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[14]
A-443654	DMLMU63	Discovery agent	N.A.	Investigative	[15]
A-674563	DMJ83LK	Discovery agent	N.A.	Investigative	[16]
Akt inhibitor VIII	DMDVIT1	Discovery agent	N.A.	Investigative	[17]
ALM-301	DMY1OG7	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[18]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[19]
BX-517	DMBQIEF	Discovery agent	N.A.	Investigative	[11]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[18]
Inositol 1,3,4,5-Tetrakisphosphate	DMIFD35	Discovery agent	N.A.	Investigative	[20]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[18]
Lactoquinomycin	DMZ0O1X	Haematological malignancy	2B33.Y	Investigative	[21]
LD-101	DMD5GO0	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
MYRIOCIN	DMVXW4L	Discovery agent	N.A.	Investigative	[10]
NU-1001-41	DMEHMOK	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
PMID20005102C1	DMMESBW	Discovery agent	N.A.	Investigative	[22]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[18]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[18]
SB-747651A	DM20Q5O	Discovery agent	N.A.	Investigative	[23]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[18]
VLI-27	DM95KRY	Pancreatic cancer	2C10	Investigative	[6]

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	2.63E-29	0.65	1.45
Rectal cancer	2C82	Rectal colon tissue	1.91E-01	0.14	0.88
Colon cancer	2C82	Colon tissue	4.61E-02	-0.04	-0.1
Multiple myeloma	2C82	Bone marrow	4.43E-02	0.23	0.73

References

• [1] Clinical pipeline report, company report or official report of Genentech (2011).
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [5] Pre-clinical and Clinical Safety Studies of CMX-2043: a cytoprotective lipoic acid analogue for ischaemia-reperfusion injury. Basic Clin Pharmacol Toxicol. 2014 Nov;115(5):456-64.
• [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. (Target id: 1479).
• [7] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
• [8] Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in cli... J Med Chem. 2009 Dec 10;52(23):7360-3.
• [9] Cancer stem cell (CSC) inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jul;27(7):753-761.
• [10] Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation. Nat Chem Biol. 2008 Sep;4(9):538-47.
• [11] Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity. Bioorg Med Chem Lett. 2007 Jul 15;17(14):3814-8.
• [12] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [13] A phthalide with in vitro growth inhibitory activity from an oidiodendron strain. J Nat Prod. 2004 Dec;67(12):2086-9.
• [14] 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
• [15] Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. J Med Chem. 2007 Jun 28;50(13):2990-3003.
• [16] Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.
• [17] Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4.
• [18] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [19] Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitum... J Med Chem. 2005 Sep 8;48(18):5639-43.
• [20] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [21] The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9.
• [22] 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.
• [23] Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-o... J Med Chem. 2008 Sep 25;51(18):5663-79.