Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLPESF3)

• DOT Name: Extracellular matrix organizing protein FRAS1 (FRAS1)
• Synonyms: Fraser syndrome 1 protein
• Gene Name: FRAS1
• Related Disease:
  Fraser syndrome
  Fraser syndrome 1
  Advanced cancer
  Bilateral renal agenesis
  Brachydactyly
  Clubfoot
  Congenital diaphragmatic hernia
  Gastric cancer
  Oculotrichoanal syndrome
  Polydactyly
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Stomach cancer
  Syndactyly
  Renal agenesis, unilateral
  Cryptophthalmia
  Ovarian neoplasm
• UniProt ID: FRAS1_HUMAN
• Pfam ID: PF16184 ; PF03160 ; PF00093
• Sequence:
  MGVLKVWLGLALALAEFAVLPHHSEGACVYQDSLLADATIWKPDSCQSCRCHGDIVICKP
  AVCRNPQCAFEKGEVLQIAANQCCPECVLRTPGSCHHEKKIHEHGTEWASSPCSVCSCNH
  GEVRCTPQPCPPLSCGHQELAFIPEGSCCPVCVGLGKPCSYEGHVFQDGEDWRLSRCAKC
  LCRNGVAQCFTAQCQPLFCNQDETVVRVPGKCCPQCSARSCSAAGQVYEHGEQWSENACT
  TCICDRGEVRCHKQACLPLRCGKGQSRARRHGQCCEECVSPAGSCSYDGVVRYQDEMWKG
  SACEFCMCDHGQVTCQTGECAKVECARDEELIHLDGKCCPECISRNGYCVYEETGEFMSS
  NASEVKRIPEGEKWEDGPCKVCECRGAQVTCYEPSCPPCPVGTLALEVKGQCCPDCTSVH
  CHPDCLTCSQSPDHCDLCQDPTKLLQNGWCVHSCGLGFYQAGSLCLACQPQCSTCTSGLE
  CSSCQPPLLMRHGQCVPTCGDGFYQDRHSCAVCHESCAGCWGPTEKHCLACRDPLHVLRD
  GGCESSCGKGFYNRQGTCSACDQSCDSCGPSSPRCLTCTEKTVLHDGKCMSECPGGYYAD
  ATGRCKVCHNSCASCSGPTPSHCTACSPPKALRQGHCLPRCGEGFYSDHGVCKACHSSCL
  ACMGPAPSHCTGCKKPEEGLQVEQLSDVGIPSGECLAQCRAHFYLESTGICEACHQSCFR
  CAGKSPHNCTDCGPSHVLLDGQCLSQCPDGYFHQEGSCTECHPTCRQCHGPLESDCISCY
  PHISLTNGNCRTSCREEQFLNLVGYCADCHHLCQHCAADLHNTGSICLRCQNAHYLLLGD
  HCVPDCPSGYYAERGACKKCHSSCRTCQGRGPFSCSSCDTNLVLSHTGTCSTTCFPGHYL
  DDNHVCQPCNTHCGSCDSQASCTSCRDPNKVLLFGECQYESCAPQYYLDFSTNTCKECDW
  SCSACSGPLKTDCLQCMDGYVLQDGACVEQCLSSFYQDSGLCKNCDSYCLQCQGPHECTR
  CKGPFLLLEAQCVQECGKGYFADHAKHKCTACPQGCLQCSHRDRCHLCDHGFFLKSGLCV
  YNCVPGFSVHTSNETCSGKIHTPSLHVNGSLILPIGSIKPLDFSLLNVQDQEGRVEDLLF
  HVVSTPTNGQLVLSRNGKEVQLDKAGRFSWKDVNEKKVRFVHSKEKLRKGYLFLKISDQQ
  FFSEPQLINIQAFSTQAPYVLRNEVLHISRGERATITTQMLDIRDDDNPQDVVIEIIDPP
  LHGQLLQTLQSPATPIYQFQLDELSRGLLHYAHDGSDSTSDVAVLQANDGHSFHNILFQV
  KTVPQNDRGLQLVANSMVWVPEGGMLQITNRILQAEAPGASAEEIIYKITQDYPQFGEVV
  LLVNMPADSPADEGQHLPDGRTATPTSTFTQQDINEGIVWYRHSGAPAQSDSFRFEVSSA
  SNAQTRLESHMFNIAILPQTPEAPKVSLEASLHMTAREDGLTVIQPHSLSFINSEKPSGK
  IVYNITLPLHPNQGIIEHRDHPHSPIRYFTQEDINQGKVMYRPPPAAPHLQELMAFSFAG
  LPESVKFHFTVSDGEHTSPEMVLTIHLLPSDQQLPVFQVTAPRLAVSPGGSTSVGLQVVV
  RDAETAPKELFFELRRPPQHGVLLKHTAEFRRPMATGDTFTYEDVEKNALQYIHDGSSTR
  EDSMEISVTDGLTVTMLEVRVEVSLSEDRGPRLAAGSSLSITVASKSTAIITRSHLAYVD
  DSSPDPEIWIQLNYLPSYGTLLRISGSEVEELSEVSNFTMEDINNKKIRYSAVFETDGHL
  VTDSFYFSVSDMDHNHLDNQIFTIMITPAENPPPVIAFADLITVDEGGRAPLSFHHFFAT
  DDDDNLQRDAIIKLSALPKYGCIENTGTGDRFGPETASDLEASFPIQDVLENYIYYFQSV
  HESIEPTHDIFSFYVSDGTSRSEIHSINITIERKNDEPPRMTLQPLRVQLSSGVVISNSS
  LSLQDLDTPDNELIFVLTKKPDHGHVLWRQTASEPLENGRVLVQGSTFTYQDILAGLVGY
  VPSVPGMVVDEFQFSLTDGLHVDTGRMKIYTELPASDTPHLAINQGLQLSAGSVARITEQ
  HLKVTDIDSDDHQVMYIMKEDPGAGRLQMMKHGNLEQISIKGPIRSFTQADISQGQPEYS
  HGTGEPGGSFAFKFDVVDGEGNRLIDKSFSISISEDKSPPVITTNKGLVLDENSVKKITT
  LQLSATDQDSGPTELIYRITRQPQLGHLEHAASPGIQISSFTQADLTSRNVQYVHSSEAE
  KHSDAFSFTLSDGVSEVTQTFHITLHPVDDSLPVVQNLGMRVQEGMRKTITEFELKAVDA
  DTEAESVTFTIVQPPRHGTIERTSNGQHFHLTSTFTMKDIYQNRVSYSHDGSNSLKDRFT
  FTVSDGTNPFFIIEEGGKEIMTAAPQPFRVDILPVDDGTPRIVTNLGLQWLEYMDGKATN
  LITKKELLTMDPDTEDAQLVYEITTGPKHGFVENKLQPGRAAATFTQEDVNLGLIRYVLH
  KEKIREMMDSFQFLVKDSKPNVVSDNVFHIQWSLISFKYTSYNVSEKAGSVSVTVQRTGN
  LNQYAIVLCRTEQGTASSSSQPGQQDYVEYAGQVQFDEREDTKSCTIVINDDDVFENVES
  FTVELSMPAYALLGEFTQAKVIINDTEDEPTLEFDKKIYWVNESAGFLFAPIERKGDASS
  IVSAICYTVPKSAMGSLFYALESGSDFKSRGMSAASRVIFGPGVTMSTCDVMLIDDSEYE
  EEEEFEIALADASDNARIGRVATAKVLISGPNDASTVSLGNTAFTVSEDAGTVKIPVIRH
  GTDLSTFASVWCATRPSDPASATPGVDYVPSSRKVEFGPGVIEQYCTLTILDDTQYPVIE
  GLETFVVFLSSAQGAELTKPFQAVIAINDTFQDVPSMQFAKDLLLVKEKEGVLHVPITRS
  GDLSYESSVRCYTQSHSAQVMEDFEERQNADSSRITFLKGDKVKNCTVYIHDDSMFEPEE
  QFRVYLGLPLGNHWSGARIGKNNMATITISNDEDAPTIEFEEAAYQVREPAGPDAIAILN
  IKVIRRGDQNRTSKVRCSTRDGSAQSGVDYYPKSRVLKFSPGVDHIFFKVEILSNEDREW
  HESFSLVLGPDDPVEAVLGDVTTATVTILDQEAAGSLILPAPPIVVTLADYDHVEEVTKE
  GVKKSPSPGYPLVCVTPCDPHFPRYAVMKERCSEAGINQTSVQFSWEVAAPTDGNGARSP
  FETITDNTPFTSVNHMVLDSIYFSRRFHVRCVAKAVDKVGHVGTPLRSNIVTIGTDSAIC
  HTPVVAGTSRGFQAQSFIATLKYLDVKHKEHPNRIHISVQIPHQDGMLPLISTMPLHNLH
  FLLSESIYRHQHVCSNLVTTYDLRGLAEAGFLDDVVYDSTALGPGYDRPFQFDPSVREPK
  TIQLYKHLNLKSCVWTFDAYYDMTELIDVCGGSVTADFQVRDSAQSFLTVHVPLYVSYIY
  VTAPRGWASLEHHTEMEFSFFYDTVLWRTGIQTDSVLSARLQIIRIYIREDGRLVIEFKT
  HAKFRGQFVMEHHTLPEVKSFVLTPDHLGGIEFDLQLLWSAQTFDSPHQLWRATSSYNRK
  DYSGEYTIYLIPCTVQPTQPWVDPGEKPLACTAHAPERFLIPIAFQQTNRPVPVVYSLNT
  EFQLCNNEKVFLMDPNTSDMSLAEMDYKGAFSKGQILYGRVLWNPEQNLNSAYKLQLEKV
  YLCTGKDGYVPFFDPTGTIYNEGPQYGCIQPNKHLKHRFLLLDRNQPEVTDKYFHDVPFE
  AHFASELPDFHVVSNMPGVDGFTLKVDALYKVEAGHQWYLQVIYIIGPDTISGPRVQRSL
  TAPLRRNRRDLVEPDGQLILDDSLIYDNEGDQVKNGTNMKSLNLEMQELAVAASLSQTGA
  SIGSALAAIMLLLLVFLVACFINRKCQKQRKKKPAEDILEEYPLNTKVEVPKRHPDRVEK
  NVNRHYCTVRNVNILSEPEAAYTFKGAKVKRLNLEVRVHNNLQDGTEV
• Function: Involved in extracellular matrix organization. Required for the regulation of epidermal-basement membrane adhesion responsible for proper organogenesis during embryonic development. Involved in brain organization and function.
• Tissue Specificity: Expressed in many adult tissues, with highest levels in kidney, pancreas and thalamus. Relatively high expression was also detected in fetal kidney and heart.
• KEGG Pathway: ECM-receptor interaction (hsa04512)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fraser syndrome	DISCLC2B	Definitive	Autosomal recessive	[1]
Fraser syndrome 1	DISOH38D	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bilateral renal agenesis	DISOR5IA	Strong	Biomarker	[4]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[5]
Clubfoot	DISLXT4S	Strong	Biomarker	[6]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Genetic Variation	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Oculotrichoanal syndrome	DIS5GWU7	Strong	Genetic Variation	[9]
Polydactyly	DIS25BMZ	Strong	Biomarker	[9]
Renal agenesis	DIS0M9AF	Strong	Biomarker	[4]
Renal hypodysplasia/aplasia 1	DISOH8XN	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Syndactyly	DISZK2BT	Strong	Biomarker	[10]
Renal agenesis, unilateral	DIS53ZJ8	Supportive	Autosomal dominant	[11]
Cryptophthalmia	DISUKC3X	Limited	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[21]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Extracellular matrix organizing protein FRAS1 (FRAS1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Extracellular matrix organizing protein FRAS1 (FRAS1).	[24]

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] Fraser syndrome due to homozygosity for a splice site mutation of FREM2. Am J Med Genet A. 2008 Feb 15;146A(4):529-31. doi: 10.1002/ajmg.a.32091.
• [3] Elucidating mechanisms of sunitinib resistance in renal cancer: an integrated pathological-molecular analysis.Oncotarget. 2017 Dec 8;9(4):4661-4674. doi: 10.18632/oncotarget.23163. eCollection 2018 Jan 12.
• [4] Sprouty1 haploinsufficiency prevents renal agenesis in a model of Fraser syndrome.J Am Soc Nephrol. 2012 Nov;23(11):1790-6. doi: 10.1681/ASN.2012020146. Epub 2012 Oct 11.
• [5] Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1.Congenit Anom (Kyoto). 2017 May;57(3):83-85. doi: 10.1111/cga.12188.
• [6] Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet. 2003 Jun;34(2):203-8. doi: 10.1038/ng1142.
• [7] The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.Hum Mol Genet. 2018 Jun 15;27(12):2064-2075. doi: 10.1093/hmg/ddy110.
• [8] Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer.Int J Cancer. 2020 May 15;146(10):2865-2876. doi: 10.1002/ijc.32705. Epub 2019 Oct 23.
• [9] Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome.Am J Med Genet A. 2006 Sep 15;140(18):1909-14. doi: 10.1002/ajmg.a.31399.
• [10] Syndactyly in a novel Fras1(rdf) mutant results from interruption of signals for interdigital apoptosis.Dev Dyn. 2016 Apr;245(4):497-507. doi: 10.1002/dvdy.24389. Epub 2016 Feb 24.
• [11] Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis. Kidney Int. 2012 Jan;81(2):196-200. doi: 10.1038/ki.2011.315. Epub 2011 Sep 7.
• [12] The Fras1/Frem family of extracellular matrix proteins: structure, function, and association with Fraser syndrome and the mouse bleb phenotype.Connect Tissue Res. 2008;49(3):277-82. doi: 10.1080/03008200802148025.
• [13] Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence.Front Genet. 2016 Mar 22;7:37. doi: 10.3389/fgene.2016.00037. eCollection 2016.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [20] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [23] 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.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [26] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.