Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5M2LFI)

• DOT Name: RAC-gamma serine/threonine-protein kinase (AKT3)
• Synonyms: EC 2.7.11.1; Protein kinase Akt-3; Protein kinase B gamma; PKB gamma; RAC-PK-gamma; STK-2
• Gene Name: AKT3
• Related Disease:
  Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
  Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
  Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
  Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
  Microcephaly
• UniProt ID: AKT3_HUMAN
• PDB ID: 2X18
• EC Number: 2.7.11.1
• Pfam ID: PF00169 ; PF00069 ; PF00433
• 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.
• Tissue Specificity: In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  Platinum drug resistance (hsa01524)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  HIF-1 sig.ling pathway (hsa04066)
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Apoptosis (hsa04210)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Cellular senescence (hsa04218)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  VEGF sig.ling pathway (hsa04370)
  Apelin sig.ling pathway (hsa04371)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor sig.ling pathway (hsa04620)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  TNF sig.ling pathway (hsa04668)
  Neurotrophin sig.ling pathway (hsa04722)
  Cholinergic sy.pse (hsa04725)
  Dopaminergic sy.pse (hsa04728)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen sig.ling pathway (hsa04915)
  Prolactin sig.ling pathway (hsa04917)
  Thyroid hormone sig.ling pathway (hsa04919)
  Adipocytokine sig.ling pathway (hsa04920)
  Glucagon sig.ling pathway (hsa04922)
  Regulation of lipolysis in adipocytes (hsa04923)
  Relaxin sig.ling pathway (hsa04926)
  GnRH secretion (hsa04929)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholic liver disease (hsa04936)
  Carbohydrate digestion and absorption (hsa04973)
  Alzheimer disease (hsa05010)
  Spinocerebellar ataxia (hsa05017)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Re.l 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)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• 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 DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	DISWECW7	Definitive	Autosomal dominant	[1]
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1	DIS06C5U	Strong	Autosomal dominant	[2]
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	DISLITFQ	Strong	Autosomal dominant	[3]
Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome	DISWVM8Y	Supportive	Autosomal dominant	[4]
Microcephaly	DIS2GRD8	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	RAC-gamma serine/threonine-protein kinase (AKT3) affects the response to substance of Doxorubicin.	[24]
Paclitaxel	DMLB81S	Approved	RAC-gamma serine/threonine-protein kinase (AKT3) affects the response to substance of Paclitaxel.	[24]
Topotecan	DMP6G8T	Approved	RAC-gamma serine/threonine-protein kinase (AKT3) affects the response to substance of Topotecan.	[25]

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[11]
Menthol	DMG2KW7	Approved	Menthol increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[15]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[21]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[22]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of RAC-gamma serine/threonine-protein kinase (AKT3).	[23]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RAC-gamma serine/threonine-protein kinase (AKT3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of RAC-gamma serine/threonine-protein kinase (AKT3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of RAC-gamma serine/threonine-protein kinase (AKT3).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012 Apr 12;74(1):41-8. doi: 10.1016/j.neuron.2012.03.010.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012 Jun 24;44(8):934-40. doi: 10.1038/ng.2331.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells. Anticancer Res. 2015 Feb;35(2):767-74.
• [15] Curcumin inhibits esophageal squamous cell carcinoma progression through down-regulating the circNRIP1/miR-532-3p/AKT pathway. Environ Toxicol. 2023 Nov;38(11):2705-2716. doi: 10.1002/tox.23905. Epub 2023 Jul 20.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.
• [23] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [24] Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol. Apoptosis. 2008 Feb;13(2):259-71. doi: 10.1007/s10495-007-0165-6.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.