Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT90X9LN)

• DOT Name: Forkhead box protein O4 (FOXO4)
• Synonyms: Fork head domain transcription factor AFX1
• Gene Name: FOXO4
• Related Disease:
  Arthritis
  Acute leukaemia
  Adult lymphoma
  Advanced cancer
  Aortic aneurysm
  Arteriosclerosis
  Atherosclerosis
  B-cell lymphoma
  B-cell neoplasm
  Bladder cancer
  Cardiovascular disease
  Clear cell renal carcinoma
  Colitis
  Colorectal carcinoma
  Epilepsy
  Gastric cancer
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Huntington disease
  Inflammatory bowel disease
  Liver cancer
  Lymphoma
  Malignant soft tissue neoplasm
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Osteoarthritis
  Paraplegia
  Pediatric lymphoma
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Sarcoma
  Stomach cancer
  Systemic lupus erythematosus
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Carcinoma
  Female hypogonadism
  Gastric ulcer
  Metastatic malignant neoplasm
  Type-1/2 diabetes
  Abdominal aortic aneurysm
  Acute myelogenous leukaemia
  Myocardial infarction
  Nasopharyngeal carcinoma
  Spinocerebellar ataxia type 3
• UniProt ID: FOXO4_HUMAN
• PDB ID: 1E17; 3L2C
• Pfam ID: PF00250 ; PF16676
• Sequence:
  MDPGNENSATEAAAIIDLDPDFEPQSRPRSCTWPLPRPEIANQPSEPPEVEPDLGEKVHT
  EGRSEPILLPSRLPEPAGGPQPGILGAVTGPRKGGSRRNAWGNQSYAELISQAIESAPEK
  RLTLAQIYEWMVRTVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIKVHNEATGKSSWWML
  NPEGGKSGKAPRRRAASMDSSSKLLRGRSKAPKKKPSVLPAPPEGATPTSPVGHFAKWSG
  SPCSRNREEADMWTTFRPRSSSNASSVSTRLSPLRPESEVLAEEIPASVSSYAGGVPPTL
  NEGLELLDGLNLTSSHSLLSRSGLSGFSLQHPGVTGPLHTYSSSLFSPAEGPLSAGEGCF
  SSSQALEALLTSDTPPPPADVLMTQVDPILSQAPTLLLLGGLPSSSKLATGVGLCPKPLE
  APGPSSLVPTLSMIAPPPVMASAPIPKALGTPVLTPPTEAASQDRMPQDLDLDMYMENLE
  CDMDNIISDLMDEGEGLDFNFEPDP
• Function: Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity.
• Tissue Specificity: Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform zeta is most abundant in the liver, kidney, and pancreas.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  FoxO sig.ling pathway (hsa04068)
  Shigellosis (hsa05131)
• Reactome Pathway:
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Ub-specific processing proteases (R-HSA-5689880)
  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)
  Cardiogenesis (R-HSA-9733709)
  AKT phosphorylates targets in the nucleus (R-HSA-198693)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Aortic aneurysm	DISQ5KRA	Strong	Altered Expression	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[7]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[8]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[7]
Colitis	DISAF7DD	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Epilepsy	DISBB28L	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Biomarker	[13]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Huntington disease	DISQPLA4	Strong	Altered Expression	[16]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[17]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[18]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[20]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[21]
Osteoarthritis	DIS05URM	Strong	Biomarker	[22]
Paraplegia	DISSKWBI	Strong	Biomarker	[23]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[24]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[24]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[25]
Sarcoma	DISZDG3U	Strong	Biomarker	[18]
Stomach cancer	DISKIJSX	Strong	Biomarker	[13]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[26]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[8]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	moderate	Biomarker	[28]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[29]
Gastric ulcer	DISBBGVO	moderate	Biomarker	[30]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[20]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[31]
Abdominal aortic aneurysm	DISD06OF	Limited	Biomarker	[32]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[33]
Myocardial infarction	DIS655KI	Limited	Altered Expression	[34]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[35]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[36]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Forkhead box protein O4 (FOXO4) decreases the response to substance of Resveratrol.	[59]

21 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 O4 (FOXO4).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Forkhead box protein O4 (FOXO4).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein O4 (FOXO4).	[39]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Forkhead box protein O4 (FOXO4).	[41]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Forkhead box protein O4 (FOXO4).	[42]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Forkhead box protein O4 (FOXO4).	[43]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Forkhead box protein O4 (FOXO4).	[43]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Forkhead box protein O4 (FOXO4).	[44]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Forkhead box protein O4 (FOXO4).	[45]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Forkhead box protein O4 (FOXO4).	[46]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Forkhead box protein O4 (FOXO4).	[47]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Forkhead box protein O4 (FOXO4).	[48]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Forkhead box protein O4 (FOXO4).	[38]
AT7519	DMCE08M	Phase 1	AT7519 increases the expression of Forkhead box protein O4 (FOXO4).	[51]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Forkhead box protein O4 (FOXO4).	[52]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Forkhead box protein O4 (FOXO4).	[53]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Forkhead box protein O4 (FOXO4).	[54]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Forkhead box protein O4 (FOXO4).	[55]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Forkhead box protein O4 (FOXO4).	[56]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Forkhead box protein O4 (FOXO4).	[57]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Forkhead box protein O4 (FOXO4).	[58]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the phosphorylation of Forkhead box protein O4 (FOXO4).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein O4 (FOXO4).	[49]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the phosphorylation of Forkhead box protein O4 (FOXO4).	[50]

References

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