Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZ9JXM)

• DOT Name: Filamin-A (FLNA)
• Synonyms: FLN-A; Actin-binding protein 280; ABP-280; Alpha-filamin; Endothelial actin-binding protein; Filamin-1; Non-muscle filamin
• Gene Name: FLNA
• Related Disease:
  FG syndrome 2
  Frontometaphyseal dysplasia 1
  Heterotopia, periventricular, X-linked dominant
  Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
  Melnick-Needles syndrome
  Otopalatodigital syndrome type 1
  Otopalatodigital syndrome type 2
  Periventricular nodular heterotopia
  Terminal osseous dysplasia-pigmentary defects syndrome
  Cardiac valvular dysplasia, X-linked
  Congenital short bowel syndrome
  Frontometaphyseal dysplasia
  X-linked Ehlers-Danlos syndrome
  Familial thoracic aortic aneurysm and aortic dissection
• UniProt ID: FLNA_HUMAN
• PDB ID: 2AAV; 2BP3; 2BRQ; 2J3S; 2JF1; 2K3T; 2K7P; 2K7Q; 2MTP; 2W0P; 2WFN; 3CNK; 3HOC; 3HOP; 3HOR; 3ISW; 3RGH; 4M9P; 4P3W; 5XR1; 6D8C; 6EW1; 7SC4; 7SFT
• Pfam ID: PF00307 ; PF00630
• Sequence:
  MSSSHSRAGQSAAGAAPGGGVDTRDAEMPATEKDLAEDAPWKKIQQNTFTRWCNEHLKCV
  SKRIANLQTDLSDGLRLIALLEVLSQKKMHRKHNQRPTFRQMQLENVSVALEFLDRESIK
  LVSIDSKAIVDGNLKLILGLIWTLILHYSISMPMWDEEEDEEAKKQTPKQRLLGWIQNKL
  PQLPITNFSRDWQSGRALGALVDSCAPGLCPDWDSWDASKPVTNAREAMQQADDWLGIPQ
  VITPEEIVDPNVDEHSVMTYLSQFPKAKLKPGAPLRPKLNPKKARAYGPGIEPTGNMVKK
  RAEFTVETRSAGQGEVLVYVEDPAGHQEEAKVTANNDKNRTFSVWYVPEVTGTHKVTVLF
  AGQHIAKSPFEVYVDKSQGDASKVTAQGPGLEPSGNIANKTTYFEIFTAGAGTGEVEVVI
  QDPMGQKGTVEPQLEARGDSTYRCSYQPTMEGVHTVHVTFAGVPIPRSPYTVTVGQACNP
  SACRAVGRGLQPKGVRVKETADFKVYTKGAGSGELKVTVKGPKGEERVKQKDLGDGVYGF
  EYYPMVPGTYIVTITWGGQNIGRSPFEVKVGTECGNQKVRAWGPGLEGGVVGKSADFVVE
  AIGDDVGTLGFSVEGPSQAKIECDDKGDGSCDVRYWPQEAGEYAVHVLCNSEDIRLSPFM
  ADIRDAPQDFHPDRVKARGPGLEKTGVAVNKPAEFTVDAKHGGKAPLRVQVQDNEGCPVE
  ALVKDNGNGTYSCSYVPRKPVKHTAMVSWGGVSIPNSPFRVNVGAGSHPNKVKVYGPGVA
  KTGLKAHEPTYFTVDCAEAGQGDVSIGIKCAPGVVGPAEADIDFDIIRNDNDTFTVKYTP
  RGAGSYTIMVLFADQATPTSPIRVKVEPSHDASKVKAEGPGLSRTGVELGKPTHFTVNAK
  AAGKGKLDVQFSGLTKGDAVRDVDIIDHHDNTYTVKYTPVQQGPVGVNVTYGGDPIPKSP
  FSVAVSPSLDLSKIKVSGLGEKVDVGKDQEFTVKSKGAGGQGKVASKIVGPSGAAVPCKV
  EPGLGADNSVVRFLPREEGPYEVEVTYDGVPVPGSPFPLEAVAPTKPSKVKAFGPGLQGG
  SAGSPARFTIDTKGAGTGGLGLTVEGPCEAQLECLDNGDGTCSVSYVPTEPGDYNINILF
  ADTHIPGSPFKAHVVPCFDASKVKCSGPGLERATAGEVGQFQVDCSSAGSAELTIEICSE
  AGLPAEVYIQDHGDGTHTITYIPLCPGAYTVTIKYGGQPVPNFPSKLQVEPAVDTSGVQC
  YGPGIEGQGVFREATTEFSVDARALTQTGGPHVKARVANPSGNLTETYVQDRGDGMYKVE
  YTPYEEGLHSVDVTYDGSPVPSSPFQVPVTEGCDPSRVRVHGPGIQSGTTNKPNKFTVET
  RGAGTGGLGLAVEGPSEAKMSCMDNKDGSCSVEYIPYEAGTYSLNVTYGGHQVPGSPFKV
  PVHDVTDASKVKCSGPGLSPGMVRANLPQSFQVDTSKAGVAPLQVKVQGPKGLVEPVDVV
  DNADGTQTVNYVPSREGPYSISVLYGDEEVPRSPFKVKVLPTHDASKVKASGPGLNTTGV
  PASLPVEFTIDAKDAGEGLLAVQITDPEGKPKKTHIQDNHDGTYTVAYVPDVTGRYTILI
  KYGGDEIPFSPYRVRAVPTGDASKCTVTVSIGGHGLGAGIGPTIQIGEETVITVDTKAAG
  KGKVTCTVCTPDGSEVDVDVVENEDGTFDIFYTAPQPGKYVICVRFGGEHVPNSPFQVTA
  LAGDQPSVQPPLRSQQLAPQYTYAQGGQQTWAPERPLVGVNGLDVTSLRPFDLVIPFTIK
  KGEITGEVRMPSGKVAQPTITDNKDGTVTVRYAPSEAGLHEMDIRYDNMHIPGSPLQFYV
  DYVNCGHVTAYGPGLTHGVVNKPATFTVNTKDAGEGGLSLAIEGPSKAEISCTDNQDGTC
  SVSYLPVLPGDYSILVKYNEQHVPGSPFTARVTGDDSMRMSHLKVGSAADIPINISETDL
  SLLTATVVPPSGREEPCLLKRLRNGHVGISFVPKETGEHLVHVKKNGQHVASSPIPVVIS
  QSEIGDASRVRVSGQGLHEGHTFEPAEFIIDTRDAGYGGLSLSIEGPSKVDINTEDLEDG
  TCRVTYCPTEPGNYIINIKFADQHVPGSPFSVKVTGEGRVKESITRRRRAPSVANVGSHC
  DLSLKIPEISIQDMTAQVTSPSGKTHEAEIVEGENHTYCIRFVPAEMGTHTVSVKYKGQH
  VPGSPFQFTVGPLGEGGAHKVRAGGPGLERAEAGVPAEFSIWTREAGAGGLAIAVEGPSK
  AEISFEDRKDGSCGVAYVVQEPGDYEVSVKFNEEHIPDSPFVVPVASPSGDARRLTVSSL
  QESGLKVNQPASFAVSLNGAKGAIDAKVHSPSGALEECYVTEIDQDKYAVRFIPRENGVY
  LIDVKFNGTHIPGSPFKIRVGEPGHGGDPGLVSAYGAGLEGGVTGNPAEFVVNTSNAGAG
  ALSVTIDGPSKVKMDCQECPEGYRVTYTPMAPGSYLISIKYGGPYHIGGSPFKAKVTGPR
  LVSNHSLHETSSVFVDSLTKATCAPQHGAPGPGPADASKVVAKGLGLSKAYVGQKSSFTV
  DCSKAGNNMLLVGVHGPRTPCEEILVKHVGSRLYSVSYLLKDKGEYTLVVKWGDEHIPGS
  PYRVVVP
• Function: Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNB may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking. Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance. During the axon guidance process, required for growth cone collapse induced by SEMA3A-mediated stimulation of neurons.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Focal adhesion (hsa04510)
  Salmonella infection (hsa05132)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  GP1b-IX-V activation signalling (R-HSA-430116)
  Cell-extracellular matrix interactions (R-HSA-446353)
  RHO GTPases activate PAKs (R-HSA-5627123)
  OAS antiviral response (R-HSA-8983711)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
FG syndrome 2	DISSL641	Definitive	X-linked recessive	[1]
Frontometaphyseal dysplasia 1	DIS2MB3L	Definitive	X-linked	[2]
Heterotopia, periventricular, X-linked dominant	DISP6LBO	Definitive	X-linked dominant	[3]
Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked	DIS5GATC	Definitive	X-linked	[4]
Melnick-Needles syndrome	DIS0KTGM	Definitive	X-linked dominant	[5]
Otopalatodigital syndrome type 1	DISL8CE9	Definitive	X-linked recessive	[6]
Otopalatodigital syndrome type 2	DISHMBG5	Definitive	X-linked	[6]
Periventricular nodular heterotopia	DISU3ZRI	Definitive	X-linked	[7]
Terminal osseous dysplasia-pigmentary defects syndrome	DISJ0KWQ	Definitive	X-linked	[4]
Cardiac valvular dysplasia, X-linked	DISN2WU4	Strong	X-linked	[8]
Congenital short bowel syndrome	DIS2A1HB	Supportive	Autosomal recessive	[9]
Frontometaphyseal dysplasia	DISXFPAW	Supportive	Autosomal dominant	[10]
X-linked Ehlers-Danlos syndrome	DISQXOLC	Supportive	X-linked	[11]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Limited	X-linked	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Filamin-A (FLNA) increases the response to substance of Artesunate.	[39]

7 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 Filamin-A (FLNA).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the phosphorylation of Filamin-A (FLNA).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Filamin-A (FLNA).	[32]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Filamin-A (FLNA).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Filamin-A (FLNA).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Filamin-A (FLNA).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Filamin-A (FLNA).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Filamin-A (FLNA).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Filamin-A (FLNA).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Filamin-A (FLNA).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Filamin-A (FLNA).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Filamin-A (FLNA).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Filamin-A (FLNA).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Filamin-A (FLNA).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Filamin-A (FLNA).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Filamin-A (FLNA).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Filamin-A (FLNA).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Filamin-A (FLNA).	[24]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Filamin-A (FLNA).	[25]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Filamin-A (FLNA).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Filamin-A (FLNA).	[28]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Filamin-A (FLNA).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Filamin-A (FLNA).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Filamin-A (FLNA).	[24]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Filamin-A (FLNA).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Filamin-A (FLNA).	[36]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Filamin-A (FLNA).	[37]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Filamin-A (FLNA).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Filamin-A (FLNA).	[27]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Filamin-A (FLNA).	[31]

References

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• [2] Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype. Am J Med Genet A. 2017 Jul;173(7):1739-1746. doi: 10.1002/ajmg.a.38267. Epub 2017 May 12.
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• [5] Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. doi: 10.1038/ng1119. Epub 2003 Mar 3.
• [6] A novel 9 bp deletion in the filamin a gene causes an otopalatodigital-spectrum disorder with a variable, intermediate phenotype. Am J Med Genet A. 2005 Feb 1;132A(4):386-90. doi: 10.1002/ajmg.a.30484.
• [7] 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.
• [8] Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007 Jan 2;115(1):40-9. doi: 10.1161/CIRCULATIONAHA.106.622621. Epub 2006 Dec 26.
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• [11] Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA. Am J Med Genet A. 2017 Jan;173(1):169-176. doi: 10.1002/ajmg.a.38004. Epub 2016 Oct 14.
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• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [23] Filamin A phosphorylation by Akt promotes cell migration in response to arsenic. Oncotarget. 2015 May 20;6(14):12009-19. doi: 10.18632/oncotarget.3617.
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• [36] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [37] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [38] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [39] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.