Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Forkhead box protein O1A (FOXO1)
• Synonyms: Forkhead in rhabdomyosarcoma; Forkhead box protein O1; FOXO1A; FKHR
• Gene Name: FOXO1
• DTT Type: Literature-reported target; [1]
• UniProt ID: FOXO1_HUMAN
• TTD ID: T72850
• 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. 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. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC and PCK1. 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 (By similarity).
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  AMPK signaling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Cellular senescence (hsa04218)
  Insulin signaling pathway (hsa04910)
  Thyroid hormone signaling pathway (hsa04919)
  Glucagon signaling pathway (hsa04922)
  Insulin resistance (hsa04931)
  AGE-RAGE signaling pathway in diabetic complications (hsa04933)
  Alcoholic liver disease (hsa04936)
  Shigellosis (hsa05131)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Transcriptional 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 DTT

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AS-1708727	DM6MWDH	Hypertriglyceridemia	5C80.1	Investigative	[1]

References

• [1] Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice. Eur J Pharmacol. 2010 Oct 25;645(1-3):185-91.