Details of Drug Off-Target (DOT)

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

• DOT Name: Forkhead box protein C1 (FOXC1)
• Synonyms: Forkhead-related protein FKHL7; Forkhead-related transcription factor 3; FREAC-3
• Gene Name: FOXC1
• Related Disease:
  Anterior segment dysgenesis 3
  Axenfeld-Rieger syndrome type 3
  Peters anomaly
  Aniridia
  Axenfeld anomaly
  Axenfeld-Rieger syndrome
  Isolated aniridia
  Rieger anomaly
• UniProt ID: FOXC1_HUMAN
• Pfam ID: PF00250
• Sequence:
  MQARYSVSSPNSLGVVPYLGGEQSYYRAAAAAAGGGYTAMPAPMSVYSHPAHAEQYPGGM
  ARAYGPYTPQPQPKDMVKPPYSYIALITMAIQNAPDKKITLNGIYQFIMDRFPFYRDNKQ
  GWQNSIRHNLSLNECFVKVPRDDKKPGKGSYWTLDPDSYNMFENGSFLRRRRRFKKKDAV
  KDKEEKDRLHLKEPPPPGRQPPPAPPEQADGNAPGPQPPPVRIQDIKTENGTCPSPPQPL
  SPAAALGSGSAAAVPKIESPDSSSSSLSSGSSPPGSLPSARPLSLDGADSAPPPPAPSAP
  PPHHSQGFSVDNIMTSLRGSPQSAAAELSSGLLASAAASSRAGIAPPLALGAYSPGQSSL
  YSSPCSQTSSAGSSGGGGGGAGAAGGAGGAGTYHCNLQAMSLYAAGERGGHLQGAPGGAG
  GSAVDDPLPDYSLPPVTSSSSSSLSHGGGGGGGGGGQEAGHHPAAHQGRLTSWYLNQAGG
  DLGHLASAAAAAAAAGYPGQQQNFHSVREMFESQRIGLNNSPVNGNSSCQMAFPSSQSLY
  RTSGAFVYDCSKF
• Function: DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development. Acts either as a transcriptional activator or repressor. Binds to the consensus binding site 5'-[G/C][A/T]AAA[T/C]AA[A/C]-3' in promoter of target genes. Upon DNA-binding, promotes DNA bending. Acts as a transcriptional coactivator. Stimulates Indian hedgehog (Ihh)-induced target gene expression mediated by the transcription factor GLI2, and hence regulates endochondral ossification. Acts also as a transcriptional coregulator by increasing DNA-binding capacity of GLI2 in breast cancer cells. Regulates FOXO1 through binding to a conserved element, 5'-GTAAACAAA-3' in its promoter region, implicating FOXC1 as an important regulator of cell viability and resistance to oxidative stress in the eye. Cooperates with transcription factor FOXC2 in regulating expression of genes that maintain podocyte integrity. Promotes cell growth inhibition by stopping the cell cycle in the G1 phase through TGFB1-mediated signals. Involved in epithelial-mesenchymal transition (EMT) induction by increasing cell proliferation, migration and invasion. Involved in chemokine CXCL12-induced endothelial cell migration through the control of CXCR4 expression. Plays a role in the gene regulatory network essential for epidermal keratinocyte terminal differentiation. Essential developmental transcriptional factor required for mesoderm-derived tissues, such as the somites, skin, bone and cartilage. Positively regulates CXCL12 and stem cell factor expression in bone marrow mesenchymal progenitor cells, and hence plays a role in the development and maintenance of mesenchymal niches for haematopoietic stem and progenitor cells (HSPC). Plays a role in corneal transparency by preventing both blood vessel and lymphatic vessel growth during embryonic development in a VEGF-dependent manner. Involved in chemokine CXCL12-induced endothelial cell migration through the control of CXCR4 expression. May function as a tumor suppressor.
• Tissue Specificity: Expressed in keratinocytes of epidermis and hair follicle . Expressed strongly in microvascular invasion (MVI) formation, basal-like breast cancer (BLBC) and hepatocellular tumors . Expressed in breast cancers (at protein level) . Expressed in hematopoietic cells .
• Reactome Pathway: Formation of intermediate mesoderm (R-HSA-9761174)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anterior segment dysgenesis 3	DISXXP4R	Definitive	Autosomal dominant	[1]
Axenfeld-Rieger syndrome type 3	DIS0YYSM	Definitive	Autosomal dominant	[2]
Peters anomaly	DISERK0M	Definitive	Autosomal dominant	[3]
Aniridia	DIS1P333	Strong	Autosomal dominant	[4]
Axenfeld anomaly	DIS15GVG	Supportive	Autosomal dominant	[5]
Axenfeld-Rieger syndrome	DIS6XY4L	Supportive	Autosomal dominant	[6]
Isolated aniridia	DISPEZG6	Supportive	Autosomal dominant	[4]
Rieger anomaly	DISNBLZ5	Supportive	Autosomal dominant	[5]

2 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 C1 (FOXC1).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Forkhead box protein C1 (FOXC1).	[30]

31 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 C1 (FOXC1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Forkhead box protein C1 (FOXC1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein C1 (FOXC1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Forkhead box protein C1 (FOXC1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Forkhead box protein C1 (FOXC1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Forkhead box protein C1 (FOXC1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Forkhead box protein C1 (FOXC1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Forkhead box protein C1 (FOXC1).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Forkhead box protein C1 (FOXC1).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Forkhead box protein C1 (FOXC1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Forkhead box protein C1 (FOXC1).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Forkhead box protein C1 (FOXC1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Forkhead box protein C1 (FOXC1).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Forkhead box protein C1 (FOXC1).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Forkhead box protein C1 (FOXC1).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Forkhead box protein C1 (FOXC1).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Forkhead box protein C1 (FOXC1).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Forkhead box protein C1 (FOXC1).	[17]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Forkhead box protein C1 (FOXC1).	[23]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Forkhead box protein C1 (FOXC1).	[24]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Forkhead box protein C1 (FOXC1).	[23]
Estrone	DM5T6US	Approved	Estrone increases the expression of Forkhead box protein C1 (FOXC1).	[23]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of Forkhead box protein C1 (FOXC1).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Forkhead box protein C1 (FOXC1).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Forkhead box protein C1 (FOXC1).	[23]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Forkhead box protein C1 (FOXC1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Forkhead box protein C1 (FOXC1).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Forkhead box protein C1 (FOXC1).	[28]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of Forkhead box protein C1 (FOXC1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Forkhead box protein C1 (FOXC1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Forkhead box protein C1 (FOXC1).	[29]

References

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