Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH6XHDU)

• DOT Name: Coagulation factor VIII (F8)
• Synonyms: Antihemophilic factor; AHF; Procoagulant component
• Gene Name: F8
• Related Disease:
  Haemophilia A
  Mild hemophilia A
  Moderately severe hemophilia A
  Severe hemophilia A
  Symptomatic form of hemophilia A in female carriers
• UniProt ID: FA8_HUMAN
• PDB ID: 1CFG; 1D7P; 1FAC; 1IQD; 2R7E; 3CDZ; 3HNB; 3HNY; 3HOB; 3J2Q; 3J2S; 4BDV; 4KI5; 4PT6; 4XZU; 5K8D; 6MF0; 6MF2; 7K66; 7KBT; 7KWO; 8G6I; 8TY1
• Pfam ID: PF07731 ; PF07732 ; PF00754
• Sequence:
  MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFN
  TSVVYKKTLFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAV
  GVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSH
  VDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRD
  AASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNH
  RQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNE
  EAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLA
  PDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTL
  LIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGP
  TKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDE
  NRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILS
  IGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRG
  MTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNSRHPSTRQKQFNATTI
  PENDIEKTDPWFAHRTPMPKIQNVSSSDLLMLLRQSPTPHGLSLSDLQEAKYETFSDDPS
  PGAIDSNNSLSEMTHFRPQLHHSGDMVFTPESGLQLRLNEKLGTTAATELKKLDFKVSST
  SNNLISTIPSDNLAAGTDNTSSLGPPSMPVHYDSQLDTTLFGKKSSPLTESGGPLSLSEE
  NNDSKLLESGLMNSQESSWGKNVSSTESGRLFKGKRAHGPALLTKDNALFKVSISLLKTN
  KTSNNSATNRKTHIDGPSLLIENSPSVWQNILESDTEFKKVTPLIHDRMLMDKNATALRL
  NHMSNKTTSSKNMEMVQQKKEGPIPPDAQNPDMSFFKMLFLPESARWIQRTHGKNSLNSG
  QGPSPKQLVSLGPEKSVEGQNFLSEKNKVVVGKGEFTKDVGLKEMVFPSSRNLFLTNLDN
  LHENNTHNQEKKIQEEIEKKETLIQENVVLPQIHTVTGTKNFMKNLFLLSTRQNVEGSYD
  GAYAPVLQDFRSLNDSTNRTKKHTAHFSKKGEEENLEGLGNQTKQIVEKYACTTRISPNT
  SQQNFVTQRSKRALKQFRLPLEETELEKRIIVDDTSTQWSKNMKHLTPSTLTQIDYNEKE
  KGAITQSPLSDCLTRSHSIPQANRSPLPIAKVSSFPSIRPIYLTRVLFQDNSSHLPAASY
  RKKDSGVQESSHFLQGAKKNNLSLAILTLEMTGDQREVGSLGTSATNSVTYKKVENTVLP
  KPDLPKTSGKVELLPKVHIYQKDLFPTETSNGSPGHLDLVEGSLLQGTEGAIKWNEANRP
  GKVPFLRVATESSAKTPSKLLDPLAWDNHYGTQIPKEEWKSQEKSPEKTAFKKKDTILSL
  NACESNHAIAAINEGQNKPEIEVTWAKQGRTERLCSQNPPVLKRHQREITRTTLQSDQEE
  IDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNR
  AQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASR
  PYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDV
  DLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRA
  PCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGH
  VFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKC
  QTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMII
  HGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFN
  PPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFA
  TWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFL
  ISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRM
  EVLGCEAQDLY
• Function: Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation (R-HSA-163841)
  COPII-mediated vesicle transport (R-HSA-204005)
  Cargo concentration in the ER (R-HSA-5694530)
  Defective factor IX causes thrombophilia (R-HSA-9672383)
  Defective F8 accelerates dissociation of the A2 domain (R-HSA-9672387)
  Defective F8 cleavage by thrombin (R-HSA-9672391)
  Defective F8 binding to von Willebrand factor (R-HSA-9672393)
  Defective F8 binding to the cell membrane (R-HSA-9672395)
  Defective cofactor function of FVIIIa variant (R-HSA-9672396)
  Defective F8 secretion (R-HSA-9672397)
  Defective F9 variant does not activate FX (R-HSA-9673202)
  Defective F8 sulfation at Y1699 (R-HSA-9674519)
  Platelet degranulation (R-HSA-114608)
• BioCyc Pathway: MetaCyc:MONOMER66-42680

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Haemophilia A	DIS0RQ2E	Definitive	X-linked	[1]
Mild hemophilia A	DISFYEEB	Supportive	X-linked	[2]
Moderately severe hemophilia A	DISWXNMO	Supportive	X-linked	[2]
Severe hemophilia A	DISXUFDW	Supportive	X-linked	[2]
Symptomatic form of hemophilia A in female carriers	DISWQ7BR	Supportive	X-linked	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Coagulation factor VIII (F8).	[3]

9 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 Coagulation factor VIII (F8).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Coagulation factor VIII (F8).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Coagulation factor VIII (F8).	[6]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Coagulation factor VIII (F8).	[7]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone increases the expression of Coagulation factor VIII (F8).	[8]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Coagulation factor VIII (F8).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Coagulation factor VIII (F8).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Coagulation factor VIII (F8).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Coagulation factor VIII (F8).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aluminium	DM6ECN9	Approved	Aluminium affects the folding of Coagulation factor VIII (F8).	[10]
Betaine	DMGRZW2	Approved	Betaine increases the secretion of Coagulation factor VIII (F8).	[11]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Hemophilia A. 2000 Sep 21 [updated 2023 Jul 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [8] von Willebrand factor and thrombin activation in children with newly diagnosed acute lymphoblastic leukemia: an impact of peripheral blasts. Pediatr Blood Cancer. 2010 Jul 1;54(7):963-9. doi: 10.1002/pbc.22466.
• [9] Aminoglycoside suppression of nonsense mutations in severe hemophilia. Blood. 2005 Nov 1;106(9):3043-8. doi: 10.1182/blood-2005-03-1307. Epub 2005 Jul 28.
• [10] Effect of metal cations on the conformation and inactivation of recombinant human factor VIII. J Pharm Sci. 2004 Oct;93(10):2549-57. doi: 10.1002/jps.20167.
• [11] Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A. PLoS One. 2012;7(9):e44505. doi: 10.1371/journal.pone.0044505. Epub 2012 Sep 4.
• [12] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.