Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEBY0TD)

• DOT Name: Hepatocyte nuclear factor 3-alpha (FOXA1)
• Synonyms: HNF-3-alpha; HNF-3A; Forkhead box protein A1; Transcription factor 3A; TCF-3A
• Gene Name: FOXA1
• Related Disease:
  Lung adenocarcinoma
  Adenocarcinoma
  Advanced cancer
  Alzheimer disease
  Bladder cancer
  Bone osteosarcoma
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Castration-resistant prostate carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Estrogen-receptor positive breast cancer
  Fatty liver disease
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Neoplasm of esophagus
  Non-alcoholic fatty liver disease
  Osteosarcoma
  Parkinson disease
  Patent ductus arteriosus
  Prostate carcinoma
  Prostate neoplasm
  Squamous cell carcinoma
  Stomach cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  Transitional cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Urothelial carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Carcinoma of esophagus
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Non-small-cell lung cancer
  Osteoporosis
  Pancreatic cancer
  Prostate cancer
  Triple negative breast cancer
• UniProt ID: FOXA1_HUMAN
• PDB ID: 7VOX
• Pfam ID: PF00250 ; PF08430 ; PF09354
• Sequence:
  MLGTVKMEGHETSDWNSYYADTQEAYSSVPVSNMNSGLGSMNSMNTYMTMNTMTTSGNMT
  PASFNMSYANPGLGAGLSPGAVAGMPGGSAGAMNSMTAAGVTAMGTALSPSGMGAMGAQQ
  AASMNGLGPYAAAMNPCMSPMAYAPSNLGRSRAGGGGDAKTFKRSYPHAKPPYSYISLIT
  MAIQQAPSKMLTLSEIYQWIMDLFPYYRQNQQRWQNSIRHSLSFNDCFVKVARSPDKPGK
  GSYWTLHPDSGNMFENGCYLRRQKRFKCEKQPGAGGGGGSGSGGSGAKGGPESRKDPSGA
  SNPSADSPLHRGVHGKTGQLEGAPAPGPAASPQTLDHSGATATGGASELKTPASSTAPPI
  SSGPGALASVPASHPAHGLAPHESQLHLKGDPHYSFNHPFSINNLMSSSEQQHKLDFKAY
  EQALQYSPYGSTLPASLPLGSASVTTRSPIEPSALEPAYYQGVYSRPVLNTS
• Function: Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3'. Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Its differential recruitment to chromatin is dependent on distribution of histone H3 methylated at 'Lys-5' (H3K4me2) in estrogen-regulated genes. Involved in the development of multiple endoderm-derived organ systems such as liver, pancreas, lung and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles. Modulates the transcriptional activity of nuclear hormone receptors. Is involved in ESR1-mediated transcription; required for ESR1 binding to the NKX2-1 promoter in breast cancer cells; binds to the RPRM promoter and is required for the estrogen-induced repression of RPRM. Involved in regulation of apoptosis by inhibiting the expression of BCL2. Involved in cell cycle regulation by activating expression of CDKN1B, alone or in conjunction with BRCA1. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis.
• Tissue Specificity: Highly expressed in prostate and ESR1-positive breast tumors. Overexpressed in esophageal and lung adenocarcinomas.
• Reactome Pathway:
  Formation of axial mesoderm (R-HSA-9796292)
  Estrogen-dependent gene expression (R-HSA-9018519)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Posttranslational Modification	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[12]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Liver cancer	DISDE4BI	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[12]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[17]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[18]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[19]
Patent ductus arteriosus	DIS9P8YS	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[21]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[23]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[24]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[24]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[25]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[24]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[26]
Urinary bladder cancer	DISDV4T7	Strong	Posttranslational Modification	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[5]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[26]
Endometrial cancer	DISW0LMR	moderate	Biomarker	[27]
Endometrial carcinoma	DISXR5CY	moderate	Biomarker	[27]
Carcinoma of esophagus	DISS6G4D	Limited	Biomarker	[17]
Esophageal cancer	DISGB2VN	Limited	Biomarker	[17]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Biomarker	[28]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[29]
Osteoporosis	DISF2JE0	Limited	Genetic Variation	[30]
Pancreatic cancer	DISJC981	Limited	Biomarker	[31]
Prostate cancer	DISF190Y	Limited	Genetic Variation	[21]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[32]

5 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 Hepatocyte nuclear factor 3-alpha (FOXA1).	[33]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Hepatocyte nuclear factor 3-alpha (FOXA1).	[41]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Hepatocyte nuclear factor 3-alpha (FOXA1).	[50]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Hepatocyte nuclear factor 3-alpha (FOXA1).	[54]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Hepatocyte nuclear factor 3-alpha (FOXA1).	[54]

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 Hepatocyte nuclear factor 3-alpha (FOXA1).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[38]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[39]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[40]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[42]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[43]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[44]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[42]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[38]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[45]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[46]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[47]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[43]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[48]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[35]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[49]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[35]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[35]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[51]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[52]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[53]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[55]
PD-153035	DM7KJTI	Discontinued in Phase 1	PD-153035 decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[56]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[35]
Choline	DM5D9YK	Investigative	Choline affects the expression of Hepatocyte nuclear factor 3-alpha (FOXA1).	[57]

References

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