Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEK6BZR)

• DOT Name: FRAS1-related extracellular matrix protein 2 (FREM2)
• Synonyms: ECM3 homolog
• Gene Name: FREM2
• Related Disease:
  Fraser syndrome 1
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Bilateral renal agenesis
  Congenital diaphragmatic hernia
  Cryptophthalmia
  Disorder of orbital region
  Glioblastoma multiforme
  Gliosarcoma
  Narcolepsy
  Oculotrichoanal syndrome
  Polydactyly
  Prostate adenocarcinoma
  Fraser syndrome 2
  Fraser syndrome
  Renal agenesis, unilateral
  Adult glioblastoma
• UniProt ID: FREM2_HUMAN
• Pfam ID: PF16184 ; PF03160 ; PF19309
• Sequence:
  MHSAGTPGLSSRRTGNSTSFQPGPPPPPRLLLLLLLLLSLVSRVPAQPAAFGRALLSPGL
  AGAAGVPAEEAIVLANRGLRVPFGREVWLDPLHDLVLQVQPGDRCAVSVLDNDALAQRPG
  RLSPKRFPCDFGPGEVRYSHLGARSPSRDRVRLQLRYDAPGGAVVLPLVLEVEVVFTQLE
  VVTRNLPLVVEELLGTSNALDARSLEFAFQPETEECRVGILSGLGALPRYGELLHYPQVP
  GGAREGGAPETLLMDCKAFQELGVRYRHTAASRSPNRDWIPMVVELRSRGAPVGSPALKR
  EHFQVLVRIRGGAENTAPKPSFVAMMMMEVDQFVLTALTPDMLAAEDAESPSDLLIFNLT
  SPFQPGQGYLVSTDDRSLPLSSFTQRDLRLLKIAYQPPSEDSDQERLFELELEVVDLEGA
  ASDPFAFMVVVKPMNTMAPVVTRNTGLILYEGQSRPLTGPAGSGPQNLVISDEDDLEAVR
  LEVVAGLRHGHLVILGASSGSSAPKSFTVAELAAGQVVYQHDDRDGSLSDNLVLRMVDGG
  GRHQVQFLFPITLVPVDDQPPVLNANTGLTLAEGETVPILPLSLSATDMDSDDSLLLFVL
  ESPFLTTGHLLLRQTHPPHEKQELLRGLWRKEGAFYERTVTEWQQQDITEGRLFYRHSGP
  HSPGPVTDQFTFRVQDNHDPPNQSGLQRFVIRIHPVDRLPPELGSGCPLRMVVQESQLTP
  LRKKWLRYTDLDTDDRELRYTVTQPPTDTDENHLPAPLGTLVLTDNPSVVVTHFTQAQIN
  HHKIAYRPPGQELGVATRVAQFQFQVEDRAGNVAPGTFTLYLHPVDNQPPEILNTGFTIQ
  EKGHHILSETELHVNDVDTDVAHISFTLTQAPKHGHMRVSGQILHVGGLFHLEDIKQGRV
  SYAHNGDKSLTDSCSLEVSDRHHVVPITLRVNVRPVDDEVPILSHPTGTLESYLDVLENG
  ATEITANVIKGTNEETDDLMLTFLLEDPPLYGEILVNGIPAEQFTQRDILEGSVVYTHTS
  GEIGLLPKADSFNLSLSDMSQEWRIGGNTIQGVTIWVTILPVDSQAPEIFVGEQLIVMEG
  DKSVITSVHISAEDVDSLNDDILCTIVIQPTSGYVENISPAPGSEKSRAGIAISAFNLKD
  LRQGHINYVQSVHKGVEPVEDRFVFRCSDGINFSERQFFPIVIIPTNDEQPEMFMREFMV
  MEGMSLVIDTPILNAADADVPLDDLTFTITQFPTHGHIMNQLINGTVLVESFTLDQIIES
  SSIIYEHDDSETQEDSFVIKLTDGKHSVEKTVLIIVIPVDDETPRMTINNGLEIEIGDTK
  IINNKILMATDLDSEDKSLVYIIRYGPGHGLLQRRKPTGAFENITLGMNFTQDEVDRNLI
  QYVHLGQEGIRDLIKFDVTDGINPLIDRYFYVSIGSIDIVFPDVISKGVSLKEGGKVTLT
  TDLLSTSDLNSPDENLVFTITRAPMRGHLECTDQPGVSITSFTQLQLAGNKIYYIHTADD
  EVKMDSFEFQVTDGRNPVFRTFRISISDVDNKKPVVTIHKLVVSESENKLITPFELTVED
  RDTPDKLLKFTITQVPIHGHLLFNNTRPVMVFTKQDLNENLISYKHDGTESSEDSFSFTV
  TDGTHTDFYVFPDTVFETRRPQVMKIQVLAVDNSVPQIAVNKGASTLRTLATGHLGFMIT
  SKILKVEDRDSLHISLRFIVTEAPQHGYLLNLDKGNHSITQFTQADIDDMKICYVLREGA
  NATSDMFYFAVEDGGGNKLTYQNFRLNWAWISFEKEYYLVNEDSKFLDVVLKRRGYLGET
  SFISIGTRDRTAEKDKDFKGKAQKQVQFNPGQTRATWRVRILSDGEHEQSETFQVVLSEP
  VLAALEFPTVATVEIVDPGDEPTVFIPQSKYSVEEDVGELFIPIRRSGDVSQELMVVCYT
  QQGTATGTVPTSVLSYSDYISRPEDHTSVVRFDKDEREKLCRIVIIDDSLYEEEETFHVL
  LSMPMGGRIGSEFPGAQVTIVPDKDDEPIFYFGDVEYSVDESAGYVEVQVWRTGTDLSKS
  SSVTVRSRKTDPPSADAGTDYVGISRNLDFAPGVNMQPVRVVILDDLGQPALEGIEKFEL
  VLRMPMNAALGEPSKATVSINDSVSDLPKMQFKERIYTGSESDGQIVTMIHRTGDVQYRS
  SVRCYTRQGSAQVMMDFEERPNTDTSIITFLPGETEKPCILELMDDVLYEEVEELRLVLG
  TPQSNSPFGAAVGEQNETLIRIRDDADKTVIKFGETKFSVTEPKEPGESVVIRIPVIRQG
  DTSKVSIVRVHTKDGSATSGEDYHPVSEEIEFKEGETQHVVEIEVTFDGVREMREAFTVH
  LKPDENMIAEMQLTKAIVYIEEMSSMADVTFPSVPQIVSLLMYDDTSKAKESAEPMSGYP
  VICITACNPKYSDYDKTGSICASENINDTLTRYRWLISAPAGPDGVTSPMREVDFDTFFT
  SSKMVTLDSIYFQPGSRVQCAARAVNTNGDEGLELMSPIVTISREEGLCQPRVPGVVGAE
  PFSAKLRYTGPEDADYTNLIKLTVTMPHIDGMLPVISTRELSNFELTLSPDGTRVGNHKC
  SNLLDYTEVKTHYGFLTDATKNPEIIGETYPYQYSLSIRGSTTLRFYRNLNLEACLWEFV
  SYYDMSELLADCGGTIGTDGQVLNLVQSYVTLRVPLYVSYVFHSPVGVGGWQHFDLKSEL
  RLTFVYDTAILWNDGIGSPPEAELQGSLYPTSMRIGDEGRLAVHFKTEAQFHGLFVLSHP
  ASFTSSVIMSADHPGLTFSLRLIRSEPTYNQPVQQWSFVSDFAVRDYSGTYTVKLVPCTA
  PSHQEYRLPVTCNPREPVTFDLDIRFQQVSDPVAAEFSLNTQMYLLSKKSLWLSDGSMGF
  GQESDVAFAEGDIIYGRVMVDPVQNLGDSFYCSIEKVFLCTGADGYVPKYSPMNAEYGCL
  ADSPSLLYRFKIVDKAQPETQATSFGNVLFNAKLAVDDPEAILLVNQPGSDGFKVDSTPL
  FQVALGREWYIHTIYTVRSKDNANRGIGKRSVEYHSLVSQGKPQSTTKSRKKREIRSTPS
  LAWEIGAENSRGTNIQHIALDRTKRQIPHGRAPPDGILPWELNSPSSAVSLVTVVGGTTV
  GLLTICLTVIAVLMCRGKESFRGKDAPKGSSSSEPMVPPQSHHNDSSEV
• Function: Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia. Required for epidermal adhesion. Involved in the development of eyelids and the anterior segment of the eyeballs.
• 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 1	DISOH38D	Definitive	Autosomal recessive	[1]
Renal agenesis	DIS0M9AF	Definitive	Biomarker	[2]
Renal hypodysplasia/aplasia 1	DISOH8XN	Definitive	Biomarker	[2]
Bilateral renal agenesis	DISOR5IA	Strong	Biomarker	[2]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[3]
Cryptophthalmia	DISUKC3X	Strong	Biomarker	[2]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[5]
Gliosarcoma	DIS985MG	Strong	Biomarker	[6]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Oculotrichoanal syndrome	DIS5GWU7	Strong	Biomarker	[4]
Polydactyly	DIS25BMZ	Strong	Biomarker	[4]
Prostate adenocarcinoma	DISBZYU8	Strong	Genetic Variation	[8]
Fraser syndrome 2	DISFCCZM	Moderate	Autosomal recessive	[9]
Fraser syndrome	DISCLC2B	Supportive	Autosomal recessive	[10]
Renal agenesis, unilateral	DIS53ZJ8	Supportive	Autosomal dominant	[11]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[12]

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 FRAS1-related extracellular matrix protein 2 (FREM2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of FRAS1-related extracellular matrix protein 2 (FREM2).	[18]

11 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 FRAS1-related extracellular matrix protein 2 (FREM2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[17]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[16]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of FRAS1-related extracellular matrix protein 2 (FREM2).	[21]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] The role of Fras1/Frem proteins in the structure and function of basement membrane.Int J Biochem Cell Biol. 2011 Apr;43(4):487-95. doi: 10.1016/j.biocel.2010.12.016. Epub 2010 Dec 21.
• [3] 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.
• [4] Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat Genet. 2005 May;37(5):520-5. doi: 10.1038/ng1549. Epub 2005 Apr 17.
• [5] High FREM2 Gene and Protein Expression Are Associated with Favorable Prognosis of IDH-WT Glioblastomas.Cancers (Basel). 2019 Jul 27;11(8):1060. doi: 10.3390/cancers11081060.
• [6] Amplification of the STOML3, FREM2, and LHFP genes is associated with mesenchymal differentiation in gliosarcoma.Am J Pathol. 2012 May;180(5):1816-23. doi: 10.1016/j.ajpath.2012.01.027.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] Integrative analysis of cancer driver genes in prostate adenocarcinoma.Mol Med Rep. 2019 Apr;19(4):2707-2715. doi: 10.3892/mmr.2019.9902. Epub 2019 Jan 28.
• [9] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [10] Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet A. 2008 Sep 1;146A(17):2252-7. doi: 10.1002/ajmg.a.32440.
• [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] Meta-Analysis and Experimental Validation Identified FREM2 and SPRY1 as New Glioblastoma Marker Candidates.Int J Mol Sci. 2018 May 4;19(5):1369. doi: 10.3390/ijms19051369.
• [13] 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.
• [14] 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.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [17] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] 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.