Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPJRB6D)

• DOT Name: Forkhead box protein O1 (FOXO1)
• Synonyms: Forkhead box protein O1A; Forkhead in rhabdomyosarcoma
• Gene Name: FOXO1
• UniProt ID: FOXO1_HUMAN
• PDB ID: 3CO6; 3CO7; 3COA; 4LG0; 5DUI; 6LBI; 6QVW; 6QZR; 6QZS; 8A62; 8A65
• Pfam ID: PF00250 ; PF16676 ; PF16675
• Sequence:
  MAEAPQVVEIDPDFEPLPRPRSCTWPLPRPEFSQSNSATSSPAPSGSAAANPDAAAGLPS
  ASAAAVSADFMSNLSLLEESEDFPQAPGSVAAAVAAAAAAAATGGLCGDFQGPEAGCLHP
  APPQPPPPGPLSQHPPVPPAAAGPLAGQPRKSSSSRRNAWGNLSYADLITKAIESSAEKR
  LTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSSWWMLN
  PEGGKSGKSPRRRAASMDNNSKFAKSRSRAAKKKASLQSGQEGAGDSPGSQFSKWPASPG
  SHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGEGDVHSMVYPPSAAKMASTLP
  SLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGTMMQQTPCYSFAPPNTSLNSPSPN
  YQKYTYGQSSMSPLPQMPIQTLQDNKSSYGGMSQYNCAPGLLKELLTSDSPPHNDIMTPV
  DPGVAQPNSRVLGQNVMMGPNSVMSTYGSQASHNKMMNPSSHTHPGHAQQTSAVNGRPLP
  HTVSTMPHTSGMNRLTQVKTPVQVPLPHPMQMSALGGYSSVSSCNGYGRMGLLHQEKLPS
  DLDGMFIERLDCDMESIIRNDLMDGDTLDFNFDNVLPNQSFPHSVKTTTHSWVSG
• Function: Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. 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. Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1. Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1. Promotes neural cell death. Mediates insulin action on adipose tissue. Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells. Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner. Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling. Positive regulator of apoptosis in cardiac smooth muscle cells as a result of its transcriptional activation of pro-apoptotic genes. Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis.
• Tissue Specificity: Expressed in umbilical endothelial cells (at protein level) . Abundantly expressed in skeletal muscle and ovary, with lower expression in the heart, placenta, lung, liver, pancreas, spleen, testis and small intestine . Weakly expressed in the brain, thymus, prostate and mucosal lining of the colon .
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Cellular senescence (hsa04218)
  Insulin sig.ling pathway (hsa04910)
  Thyroid hormone sig.ling pathway (hsa04919)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Alcoholic liver disease (hsa04936)
  Shigellosis (hsa05131)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Prostate cancer (hsa05215)
• Reactome Pathway:
  Regulation of gene expression in beta cells (R-HSA-210745)
  AKT-mediated inactivation of FOXO1A (R-HSA-211163)
  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)
  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)
  AKT phosphorylates targets in the nucleus (R-HSA-198693)

Molecular Interaction Atlas (MIA) of This DOT

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 O1 (FOXO1) decreases the response to substance of Resveratrol.	[42]

15 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 O1 (FOXO1).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the phosphorylation of Forkhead box protein O1 (FOXO1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the phosphorylation of Forkhead box protein O1 (FOXO1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[12]
Ethanol	DMDRQZU	Approved	Ethanol decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[19]
Etoposide	DMNH3PG	Approved	Etoposide increases the phosphorylation of Forkhead box protein O1 (FOXO1).	[5]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[23]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the phosphorylation of Forkhead box protein O1 (FOXO1).	[24]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein O1 (FOXO1).	[27]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[35]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the phosphorylation of Forkhead box protein O1 (FOXO1).	[36]
acrolein	DMAMCSR	Investigative	acrolein increases the phosphorylation of Forkhead box protein O1 (FOXO1).	[37]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the phosphorylation of Forkhead box protein O1 (FOXO1).	[39]

29 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 O1 (FOXO1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Forkhead box protein O1 (FOXO1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Forkhead box protein O1 (FOXO1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Forkhead box protein O1 (FOXO1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Forkhead box protein O1 (FOXO1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Forkhead box protein O1 (FOXO1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Forkhead box protein O1 (FOXO1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Forkhead box protein O1 (FOXO1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Forkhead box protein O1 (FOXO1).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Forkhead box protein O1 (FOXO1).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Forkhead box protein O1 (FOXO1).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Forkhead box protein O1 (FOXO1).	[17]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Forkhead box protein O1 (FOXO1).	[18]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Forkhead box protein O1 (FOXO1).	[14]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Forkhead box protein O1 (FOXO1).	[21]
Sodium chloride	DMM3950	Approved	Sodium chloride decreases the expression of Forkhead box protein O1 (FOXO1).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Forkhead box protein O1 (FOXO1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Forkhead box protein O1 (FOXO1).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Forkhead box protein O1 (FOXO1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Forkhead box protein O1 (FOXO1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Forkhead box protein O1 (FOXO1).	[29]
Dioscin	DM5H2W9	Preclinical	Dioscin increases the expression of Forkhead box protein O1 (FOXO1).	[30]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Forkhead box protein O1 (FOXO1).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Forkhead box protein O1 (FOXO1).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Forkhead box protein O1 (FOXO1).	[34]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Forkhead box protein O1 (FOXO1).	[38]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Forkhead box protein O1 (FOXO1).	[40]
Hydroxyestradiol	DMJXQME	Investigative	Hydroxyestradiol decreases the expression of Forkhead box protein O1 (FOXO1).	[41]
2-hydroxy-17beta-estradiol	DMM9Z0B	Investigative	2-hydroxy-17beta-estradiol decreases the expression of Forkhead box protein O1 (FOXO1).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Simvastatin decreases the localization of Forkhead box protein O1 (FOXO1).	[20]
Piperlongumine	DMIZCOE	Preclinical	Piperlongumine affects the localization of Forkhead box protein O1 (FOXO1).	[31]

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