Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHXQG4P)

• DOT Name: Forkhead box protein O3 (FOXO3)
• Synonyms: AF6q21 protein; Forkhead in rhabdomyosarcoma-like 1
• Gene Name: FOXO3
• Related Disease:
  Arteriosclerosis
  Chronic obstructive pulmonary disease
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Advanced cancer
  Atherosclerosis
  Bladder cancer
  Breast neoplasm
  Childhood acute lymphoblastic leukemia
  Chronic kidney disease
  Clear cell renal carcinoma
  Colorectal carcinoma
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Hyperglycemia
  Melanoma
  Metastatic malignant neoplasm
  Neuroblastoma
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Osteoarthritis
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult glioblastoma
  Colon cancer
  Colon carcinoma
  Glioblastoma multiforme
  Alzheimer disease
  Bone osteosarcoma
  Osteosarcoma
  Prostate neoplasm
  Schizophrenia
• UniProt ID: FOXO3_HUMAN
• PDB ID: 2K86; 2LQH; 2LQI; 2UZK; 6MNL; 7V9B
• Pfam ID: PF00250 ; PF16676 ; PF16675
• Sequence:
  MAEAPASPAPLSPLEVELDPEFEPQSRPRSCTWPLQRPELQASPAKPSGETAADSMIPEE
  EDDEDDEDGGGRAGSAMAIGGGGGSGTLGSGLLLEDSARVLAPGGQDPGSGPATAAGGLS
  GGTQALLQPQQPLPPPQPGAAGGSGQPRKCSSRRNAWGNLSYADLITRAIESSPDKRLTL
  SQIYEWMVRCVPYFKDKGDSNSSAGWKNSIRHNLSLHSRFMRVQNEGTGKSSWWIINPDG
  GKSGKAPRRRAVSMDNSNKYTKSRGRAAKKKAALQTAPESADDSPSQLSKWPGSPTSRSS
  DELDAWTDFRSRTNSNASTVSGRLSPIMASTELDEVQDDDAPLSPMLYSSSASLSPSVSK
  PCTVELPRLTDMAGTMNLNDGLTENLMDDLLDNITLPPSQPSPTGGLMQRSSSFPYTTKG
  SGLGSPTSSFNSTVFGPSSLNSLRQSPMQTIQENKPATFSSMSHYGNQTLQDLLTSDSLS
  HSDVMMTQSDPLMSQASTAVSAQNSRRNVMLRNDPMMSFAAQPNQGSLVNQNLLHHQHQT
  QGALGGSRALSNSVSNMGLSESSSLGSAKHQQQSPVSQSMQTLSDSLSGSSLYSTSANLP
  VMGHEKFPSDLDLDMFNGSLECDMESIIRSELMDADGLDFNFDSLISTQNVVGLNVGNFT
  GAKQASSQSWVPG
• Function: Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy. Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins. Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation. In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation. Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Chemokine sig.ling pathway (hsa04062)
  FoxO sig.ling pathway (hsa04068)
  Mitophagy - animal (hsa04137)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Cellular senescence (hsa04218)
  Neurotrophin sig.ling pathway (hsa04722)
  Prolactin sig.ling pathway (hsa04917)
  Alcoholic liver disease (hsa04936)
  Shigellosis (hsa05131)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Endometrial cancer (hsa05213)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway:
  AKT phosphorylates targets in the nucleus (R-HSA-198693)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (R-HSA-8862803)
  RUNX3 regulates BCL2L11 (BIM) transcription (R-HSA-8952158)
  FLT3 Signaling (R-HSA-9607240)
  Regulation of localization of FOXO transcription factors (R-HSA-9614399)
  FOXO-mediated transcription of cell death genes (R-HSA-9614657)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Regulation of FOXO transcriptional activity by acetylation (R-HSA-9617629)
  FOXO-mediated transcription of cell cycle genes (R-HSA-9617828)
  Estrogen-dependent nuclear events downstream of ESR-membrane signaling (R-HSA-9634638)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Biomarker	[1]
Chronic obstructive pulmonary disease	DISQCIRF	Definitive	Altered Expression	[2]
Epithelial ovarian cancer	DIS56MH2	Definitive	Altered Expression	[3]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[4]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[5]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Definitive	Altered Expression	[3]
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[6]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[6]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Biomarker	[14]
Glioma	DIS5RPEH	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[16]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[17]
Melanoma	DIS1RRCY	Strong	Altered Expression	[18]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[19]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[20]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[21]
Obesity	DIS47Y1K	Strong	Biomarker	[22]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[23]
Pancreatic cancer	DISJC981	Strong	Biomarker	[24]
Prostate cancer	DISF190Y	Strong	Biomarker	[25]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[25]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[26]
Stomach cancer	DISKIJSX	Strong	Biomarker	[14]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[27]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[28]
Colon cancer	DISVC52G	moderate	Biomarker	[29]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[29]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[28]
Alzheimer disease	DISF8S70	Limited	Altered Expression	[30]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[31]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[31]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[32]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[33]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Forkhead box protein O3 (FOXO3) affects the response to substance of Fluorouracil.	[77]
Gefitinib	DM15F0X	Approved	Forkhead box protein O3 (FOXO3) increases the response to substance of Gefitinib.	[78]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Forkhead box protein O3 (FOXO3).	[34]
Ethanol	DMDRQZU	Approved	Ethanol increases the phosphorylation of Forkhead box protein O3 (FOXO3).	[47]
Etoposide	DMNH3PG	Approved	Etoposide increases the phosphorylation of Forkhead box protein O3 (FOXO3).	[48]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the phosphorylation of Forkhead box protein O3 (FOXO3).	[59]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the phosphorylation of Forkhead box protein O3 (FOXO3).	[61]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein O3 (FOXO3).	[64]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the phosphorylation of Forkhead box protein O3 (FOXO3).	[67]
GSK690693	DMRBVHE	Phase 1	GSK690693 decreases the phosphorylation of Forkhead box protein O3 (FOXO3).	[69]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Forkhead box protein O3 (FOXO3).	[70]
Wortmannin	DM8EVK5	Terminated	Wortmannin decreases the phosphorylation of Forkhead box protein O3 (FOXO3).	[71]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Forkhead box protein O3 (FOXO3).	[70]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the phosphorylation of Forkhead box protein O3 (FOXO3).	[75]
Eckol	DMIVY0Q	Investigative	Eckol increases the phosphorylation of Forkhead box protein O3 (FOXO3).	[76]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Forkhead box protein O3 (FOXO3).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Forkhead box protein O3 (FOXO3).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Forkhead box protein O3 (FOXO3).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein O3 (FOXO3).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Forkhead box protein O3 (FOXO3).	[39]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Forkhead box protein O3 (FOXO3).	[40]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Forkhead box protein O3 (FOXO3).	[41]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Forkhead box protein O3 (FOXO3).	[42]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Forkhead box protein O3 (FOXO3).	[43]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Forkhead box protein O3 (FOXO3).	[44]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Forkhead box protein O3 (FOXO3).	[45]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Forkhead box protein O3 (FOXO3).	[45]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Forkhead box protein O3 (FOXO3).	[49]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Forkhead box protein O3 (FOXO3).	[49]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Forkhead box protein O3 (FOXO3).	[50]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Forkhead box protein O3 (FOXO3).	[51]
Cabazitaxel	DMPAZHC	Approved	Cabazitaxel affects the expression of Forkhead box protein O3 (FOXO3).	[52]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Forkhead box protein O3 (FOXO3).	[53]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Forkhead box protein O3 (FOXO3).	[54]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Forkhead box protein O3 (FOXO3).	[55]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Forkhead box protein O3 (FOXO3).	[56]
Buparlisib	DM1WEHC	Phase 3	Buparlisib increases the expression of Forkhead box protein O3 (FOXO3).	[57]
Remdesivir	DMBFZ6L	Phase 3 Trial	Remdesivir increases the expression of Forkhead box protein O3 (FOXO3).	[58]
PD-0325901	DM27D4J	Phase 2	PD-0325901 increases the expression of Forkhead box protein O3 (FOXO3).	[60]
TAK-715	DMZKPI8	Phase 2	TAK-715 increases the expression of Forkhead box protein O3 (FOXO3).	[63]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Forkhead box protein O3 (FOXO3).	[65]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Forkhead box protein O3 (FOXO3).	[66]
AT7519	DMCE08M	Phase 1	AT7519 increases the expression of Forkhead box protein O3 (FOXO3).	[68]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Forkhead box protein O3 (FOXO3).	[42]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Forkhead box protein O3 (FOXO3).	[41]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Forkhead box protein O3 (FOXO3).	[72]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Forkhead box protein O3 (FOXO3).	[73]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Forkhead box protein O3 (FOXO3).	[74]

6 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant affects the localization of Forkhead box protein O3 (FOXO3).	[46]
INK128	DMGO7QT	Phase 2	INK128 affects the localization of Forkhead box protein O3 (FOXO3).	[62]
G1	DMTV42K	Phase 1/2	G1 affects the localization of Forkhead box protein O3 (FOXO3).	[46]
OLEANOLIC_ACID	DMWDMJ3	Investigative	OLEANOLIC_ACID affects the localization of Forkhead box protein O3 (FOXO3).	[63]
TGX-221	DMM0LRE	Investigative	TGX-221 affects the localization of Forkhead box protein O3 (FOXO3).	[46]
PIK-75	DM9BQTX	Investigative	PIK-75 affects the localization of Forkhead box protein O3 (FOXO3).	[46]

References

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