Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYCJT63)

• DOT Name: Fibrillin-1 (FBN1)
• Gene Name: FBN1
• Related Disease:
  Familial thoracic aortic aneurysm and aortic dissection
  Marfan syndrome
  MASS syndrome
  Shprintzen-Goldberg syndrome
  Abdominal aortic aneurysm
  Acromicric dysplasia
  Advanced cancer
  Aortic aneurysm
  Brachydactyly
  Congenital diaphragmatic hernia
  Connective tissue disorder
  Craniosynostosis
  Endometriosis
  Fetal growth restriction
  Glaucoma/ocular hypertension
  Glomerulonephritis
  Hereditary disorder of connective tissue
  High blood pressure
  Liver cirrhosis
  Neoplasm
  Obesity
  Progeroid and marfanoid aspect-lipodystrophy syndrome
  Stiff skin syndrome
  Weill-Marchesani syndrome 2, dominant
  Congenital contractural arachnodactyly
  Coronary atherosclerosis
  Coronary heart disease
  Intellectual disability
  Mitral valve prolapse
  Geleophysic dysplasia
  Isolated ectopia lentis
  Neonatal Marfan syndrome
  Weill-Marchesani syndrome
  Cataract
  Ectopia lentis 1, isolated, autosomal dominant
  Hyperglycemia
  Hyperinsulinemia
  Lipodystrophy
  Loeys-Dietz syndrome
  Non-insulin dependent diabetes
• UniProt ID: FBN1_HUMAN
• PDB ID: 1APJ; 1EMN; 1EMO; 1LMJ; 1UZJ; 1UZK; 1UZP; 1UZQ; 2M74; 2W86; 5MS9
• Pfam ID: PF12662 ; PF12947 ; PF07645 ; PF21364 ; PF18193 ; PF14670 ; PF12661 ; PF00683
• Sequence:
  MRRGRLLEIALGFTVLLASYTSHGADANLEAGNVKETRASRAKRRGGGGHDALKGPNVCG
  SRYNAYCCPGWKTLPGGNQCIVPICRHSCGDGFCSRPNMCTCPSGQIAPSCGSRSIQHCN
  IRCMNGGSCSDDHCLCQKGYIGTHCGQPVCESGCLNGGRCVAPNRCACTYGFTGPQCERD
  YRTGPCFTVISNQMCQGQLSGIVCTKTLCCATVGRAWGHPCEMCPAQPHPCRRGFIPNIR
  TGACQDVDECQAIPGLCQGGNCINTVGSFECKCPAGHKLNEVSQKCEDIDECSTIPGICE
  GGECTNTVSSYFCKCPPGFYTSPDGTRCIDVRPGYCYTALTNGRCSNQLPQSITKMQCCC
  DAGRCWSPGVTVAPEMCPIRATEDFNKLCSVPMVIPGRPEYPPPPLGPIPPVLPVPPGFP
  PGPQIPVPRPPVEYLYPSREPPRVLPVNVTDYCQLVRYLCQNGRCIPTPGSYRCECNKGF
  QLDLRGECIDVDECEKNPCAGGECINNQGSYTCQCRAGYQSTLTRTECRDIDECLQNGRI
  CNNGRCINTDGSFHCVCNAGFHVTRDGKNCEDMDECSIRNMCLNGMCINEDGSFKCICKP
  GFQLASDGRYCKDINECETPGICMNGRCVNTDGSYRCECFPGLAVGLDGRVCVDTHMRST
  CYGGYKRGQCIKPLFGAVTKSECCCASTEYAFGEPCQPCPAQNSAEYQALCSSGPGMTSA
  GSDINECALDPDICPNGICENLRGTYKCICNSGYEVDSTGKNCVDINECVLNSLLCDNGQ
  CRNTPGSFVCTCPKGFIYKPDLKTCEDIDECESSPCINGVCKNSPGSFICECSSESTLDP
  TKTICIETIKGTCWQTVIDGRCEININGATLKSQCCSSLGAAWGSPCTLCQVDPICGKGY
  SRIKGTQCEDIDECEVFPGVCKNGLCVNTRGSFKCQCPSGMTLDATGRICLDIRLETCFL
  RYEDEECTLPIAGRHRMDACCCSVGAAWGTEECEECPMRNTPEYEELCPRGPGFATKEIT
  NGKPFFKDINECKMIPSLCTHGKCRNTIGSFKCRCDSGFALDSEERNCTDIDECRISPDL
  CGRGQCVNTPGDFECKCDEGYESGFMMMKNCMDIDECQRDPLLCRGGVCHNTEGSYRCEC
  PPGHQLSPNISACIDINECELSAHLCPNGRCVNLIGKYQCACNPGYHSTPDRLFCVDIDE
  CSIMNGGCETFCTNSEGSYECSCQPGFALMPDQRSCTDIDECEDNPNICDGGQCTNIPGE
  YRCLCYDGFMASEDMKTCVDVNECDLNPNICLSGTCENTKGSFICHCDMGYSGKKGKTGC
  TDINECEIGAHNCGKHAVCTNTAGSFKCSCSPGWIGDGIKCTDLDECSNGTHMCSQHADC
  KNTMGSYRCLCKEGYTGDGFTCTDLDECSENLNLCGNGQCLNAPGGYRCECDMGFVPSAD
  GKACEDIDECSLPNICVFGTCHNLPGLFRCECEIGYELDRSGGNCTDVNECLDPTTCISG
  NCVNTPGSYICDCPPDFELNPTRVGCVDTRSGNCYLDIRPRGDNGDTACSNEIGVGVSKA
  SCCCSLGKAWGTPCEMCPAVNTSEYKILCPGGEGFRPNPITVILEDIDECQELPGLCQGG
  KCINTFGSFQCRCPTGYYLNEDTRVCDDVNECETPGICGPGTCYNTVGNYTCICPPDYMQ
  VNGGNNCMDMRRSLCYRNYYADNQTCDGELLFNMTKKMCCCSYNIGRAWNKPCEQCPIPS
  TDEFATLCGSQRPGFVIDIYTGLPVDIDECREIPGVCENGVCINMVGSFRCECPVGFFYN
  DKLLVCEDIDECQNGPVCQRNAECINTAGSYRCDCKPGYRFTSTGQCNDRNECQEIPNIC
  SHGQCIDTVGSFYCLCHTGFKTNDDQTMCLDINECERDACGNGTCRNTIGSFNCRCNHGF
  ILSHNNDCIDVDECASGNGNLCRNGQCINTVGSFQCQCNEGYEVAPDGRTCVDINECLLE
  PRKCAPGTCQNLDGSYRCICPPGYSLQNEKCEDIDECVEEPEICALGTCSNTEGSFKCLC
  PEGFSLSSSGRRCQDLRMSYCYAKFEGGKCSSPKSRNHSKQECCCALKGEGWGDPCELCP
  TEPDEAFRQICPYGSGIIVGPDDSAVDMDECKEPDVCKHGQCINTDGSYRCECPFGYILA
  GNECVDTDECSVGNPCGNGTCKNVIGGFECTCEEGFEPGPMMTCEDINECAQNPLLCAFR
  CVNTYGSYECKCPVGYVLREDRRMCKDEDECEEGKHDCTEKQMECKNLIGTYMCICGPGY
  QRRPDGEGCVDENECQTKPGICENGRCLNTRGSYTCECNDGFTASPNQDECLDNREGYCF
  TEVLQNMCQIGSSNRNPVTKSECCCDGGRGWGPHCEICPFQGTVAFKKLCPHGRGFMTNG
  ADIDECKVIHDVCRNGECVNDRGSYHCICKTGYTPDITGTSCVDLNECNQAPKPCNFICK
  NTEGSYQCSCPKGYILQEDGRSCKDLDECATKQHNCQFLCVNTIGGFTCKCPPGFTQHHT
  SCIDNNECTSDINLCGSKGICQNTPGSFTCECQRGFSLDQTGSSCEDVDECEGNHRCQHG
  CQNIIGGYRCSCPQGYLQHYQWNQCVDENECLSAHICGGASCHNTLGSYKCMCPAGFQYE
  QFSGGCQDINECGSAQAPCSYGCSNTEGGYLCGCPPGYFRIGQGHCVSGMGMGRGNPEPP
  VSGEMDDNSLSPEACYECKINGYPKRGRKRRSTNETDASNIEDQSETEANVSLASWDVEK
  TAIFAFNISHVSNKVRILELLPALTTLTNHNRYLIESGNEDGFFKINQKEGISYLHFTKK
  KPVAGTYSLQISSTPLYKKKELNQLEDKYDKDYLSGELGDNLKMKIQVLLH
• Function: [Fibrillin-1]: Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues. Fibrillin-1-containing microfibrils provide long-term force bearing structural support. In tissues such as the lung, blood vessels and skin, microfibrils form the periphery of the elastic fiber, acting as a scaffold for the deposition of elastin. In addition, microfibrils can occur as elastin-independent networks in tissues such as the ciliary zonule, tendon, cornea and glomerulus where they provide tensile strength and have anchoring roles. Fibrillin-1 also plays a key role in tissue homeostasis through specific interactions with growth factors, such as the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and latent transforming growth factor-beta-binding proteins (LTBPs), cell-surface integrins and other extracellular matrix protein and proteoglycan components. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively. Negatively regulates osteoclastogenesis by binding and sequestering an osteoclast differentiation and activation factor TNFSF11. This leads to disruption of TNFSF11-induced Ca(2+) signaling and impairment of TNFSF11-mediated nuclear translocation and activation of transcription factor NFATC1 which regulates genes important for osteoclast differentiation and function. Mediates cell adhesion via its binding to cell surface receptors integrins ITGAV:ITGB3 and ITGA5:ITGB1. Binds heparin and this interaction has an important role in the assembly of microfibrils ; [Asprosin]: Adipokine secreted by white adipose tissue that plays an important regulatory role in the glucose metabolism of liver, muscle and pancreas. Hormone that targets the liver in response to fasting to increase plasma glucose levels. Binds the olfactory receptor OR4M1 at the surface of hepatocytes and promotes hepatocyte glucose release by activating the protein kinase A activity in the liver, resulting in rapid glucose release into the circulation. May act as a regulator of adaptive thermogenesis by inhibiting browning and energy consumption, while increasing lipid deposition in white adipose tissue. Also acts as an orexigenic hormone that increases appetite: crosses the blood brain barrier and exerts effects on the hypothalamus. In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation. Activates orexigenic AgRP neurons via binding to the olfactory receptor OR4M1. May also play a role in sperm motility in testis via interaction with OR4M1 receptor.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  Elastic fibre formation (R-HSA-1566948)
  Molecules associated with elastic fibres (R-HSA-2129379)
  Integrin cell surface interactions (R-HSA-216083)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Definitive	Autosomal dominant	[1]
Marfan syndrome	DISVEUWZ	Definitive	Autosomal dominant	[1]
MASS syndrome	DISI3721	Definitive	Autosomal dominant	[2]
Shprintzen-Goldberg syndrome	DISQH6P3	Definitive	Autosomal dominant	[3]
Abdominal aortic aneurysm	DISD06OF	Strong	Genetic Variation	[4]
Acromicric dysplasia	DISMV8M7	Strong	Autosomal dominant	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Aortic aneurysm	DISQ5KRA	Strong	Genetic Variation	[7]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[8]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[9]
Connective tissue disorder	DISKXBS3	Strong	Genetic Variation	[7]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[10]
Endometriosis	DISX1AG8	Strong	Biomarker	[11]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[12]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[13]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[14]
Hereditary disorder of connective tissue	DIS8I9FS	Strong	Genetic Variation	[15]
High blood pressure	DISY2OHH	Strong	Biomarker	[16]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[19]
Progeroid and marfanoid aspect-lipodystrophy syndrome	DISOPKZD	Strong	Autosomal dominant	[20]
Stiff skin syndrome	DISM2Z81	Strong	Autosomal dominant	[21]
Weill-Marchesani syndrome 2, dominant	DISQUJI6	Strong	Autosomal dominant	[22]
Congenital contractural arachnodactyly	DISOM1K7	moderate	Genetic Variation	[23]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[24]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[25]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[26]
Mitral valve prolapse	DISNCHQ3	moderate	Genetic Variation	[27]
Geleophysic dysplasia	DISZOO1G	Supportive	Autosomal dominant	[28]
Isolated ectopia lentis	DISJWTN6	Supportive	Autosomal dominant	[29]
Neonatal Marfan syndrome	DISPXPVM	Supportive	Autosomal dominant	[30]
Weill-Marchesani syndrome	DIS9B7CX	Supportive	Autosomal dominant	[31]
Cataract	DISUD7SL	Limited	Biomarker	[32]
Ectopia lentis 1, isolated, autosomal dominant	DISK44PQ	Limited	Autosomal dominant	[33]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[34]
Hyperinsulinemia	DISIDWT6	Limited	Biomarker	[35]
Lipodystrophy	DIS3SGVD	Limited	Biomarker	[36]
Loeys-Dietz syndrome	DIS4FUPZ	Limited	Genetic Variation	[37]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[38]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fibrillin-1 (FBN1).	[39]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibrillin-1 (FBN1).	[40]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibrillin-1 (FBN1).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Fibrillin-1 (FBN1).	[42]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Fibrillin-1 (FBN1).	[43]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Fibrillin-1 (FBN1).	[44]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Fibrillin-1 (FBN1).	[45]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Fibrillin-1 (FBN1).	[43]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Fibrillin-1 (FBN1).	[46]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Fibrillin-1 (FBN1).	[47]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Fibrillin-1 (FBN1).	[48]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of Fibrillin-1 (FBN1).	[49]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Fibrillin-1 (FBN1).	[43]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Fibrillin-1 (FBN1).	[50]
Guaiacol	DMN4E7T	Phase 3	Guaiacol decreases the expression of Fibrillin-1 (FBN1).	[50]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Fibrillin-1 (FBN1).	[50]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Fibrillin-1 (FBN1).	[51]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of Fibrillin-1 (FBN1).	[50]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Fibrillin-1 (FBN1).	[53]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Fibrillin-1 (FBN1).	[54]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fibrillin-1 (FBN1).	[56]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Fibrillin-1 (FBN1).	[57]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Fibrillin-1 (FBN1).	[58]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid decreases the expression of Fibrillin-1 (FBN1).	[50]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Fibrillin-1 (FBN1).	[53]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Fibrillin-1 (FBN1).	[53]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibrillin-1 (FBN1).	[52]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Fibrillin-1 (FBN1).	[55]

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