Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMZD6D4)

• DOT Name: Filamin-A-interacting protein 1 (FILIP1)
• Synonyms: FILIP
• Gene Name: FILIP1
• Related Disease:
  Leprosy
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Intellectual disability
• UniProt ID: FLIP1_HUMAN
• Pfam ID: PF09727
• Sequence:
  MRSRNQGGESASDGHISCPKPSIIGNAGEKSLSEDAKKKKKSNRKEDDVMASGTVKRHLK
  TSGECERKTKKSLELSKEDLIQLLSIMEGELQAREDVIHMLKTEKTKPEVLEAHYGSAEP
  EKVLRVLHRDAILAQEKSIGEDVYEKPISELDRLEEKQKETYRRMLEQLLLAEKCHRRTV
  YELENEKHKHTDYMNKSDDFTNLLEQERERLKKLLEQEKAYQARKEKENAKRLNKLRDEL
  VKLKSFALMLVDERQMHIEQLGLQSQKVQDLTQKLREEEEKLKAITSKSKEDRQKLLKLE
  VDFEHKASRFSQEHEEMNAKLANQESHNRQLRLKLVGLTQRIEELEETNKNLQKAEEELQ
  ELRDKIAKGECGNSSLMAEVENLRKRVLEMEGKDEEITKTESQCRELRKKLQEEEHHSKE
  LRLEVEKLQKRMSELEKLEEAFSKSKSECTQLHLNLEKEKNLTKDLLNELEVVKSRVKEL
  ECSESRLEKAELSLKDDLTKLKSFTVMLVDERKNMMEKIKQEERKVDGLNKNFKVEQGKV
  MDVTEKLIEESKKLLKLKSEMEEKVYNLTRERDELIGKLKSEEEKSSELSCSVDLLKKRL
  DGIEEVEREITRGRSRKGSELTCPEDNKIKELTLEIERLKKRLQQLEVVEGDLMKTEDEY
  DQLEQKFRTEQDKANFLSQQLEEIKHQIAKNKAIEKGEVVSQEAELRHRFRLEEAKSRDL
  KAEVQALKEKIHELMNKEDQLSQLQVDYSVLQQRFMEEENKNKNMGQEVLNLTKELELSK
  RYSRALRPSVNGRRMVDVPVTSTGVQTDAVSGEAAEEETPAVFIRKSFQEENHIMSNLRQ
  VGLKKPVERSSVLDRYPPAANELTMRKSWIPWMRKRENGPSITQEKGPRTNSSPGHPGEV
  VLSPKQGQPLHIRVTPDHENSTATLEITSPTSEEFFSSTTVIPTLGNQKPRITIIPSPNV
  MPQKQKSGDTTLGPERAMSPVTITTFSREKTPESGRGAFADRPTSPIQIMTVSTSAAPAE
  IAVSPESQEMPMGRTILKVTPEKQTVPTPVRKYNSNANIITTEDNKIHIHLGSQFKRSPG
  TSGEGVSPVITVRPVNVTAEKEVSTGTVLRSPRNHLSSRPGASKVTSTITITPVTTSSAR
  GTQSVSGQDGSSQRPTPTRIPMSKGMKAGKPVVAAPGAGNLTKFEPRAETQSMKIELKKS
  AASSTTSLGGGKG
• Function: By acting through a filamin-A/F-actin axis, it controls the start of neocortical cell migration from the ventricular zone. May be able to induce the degradation of filamin-A.
• Tissue Specificity: Moderately expressed in adult heart and brain. Weakly expressed in lung, skeletal muscle, ovary, testis, kidney, and fetal brain, and hardly detectable in liver, pancreas, spleen, and fetal liver. Within brain, moderate expression is found in amygdala and caudate nucleus.
• Reactome Pathway: RHOD GTPase cycle (R-HSA-9013405)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leprosy	DISAA4UI	moderate	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Limited	Biomarker	[2]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[2]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[3]

2 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 Filamin-A-interacting protein 1 (FILIP1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Filamin-A-interacting protein 1 (FILIP1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Filamin-A-interacting protein 1 (FILIP1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Filamin-A-interacting protein 1 (FILIP1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Filamin-A-interacting protein 1 (FILIP1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Filamin-A-interacting protein 1 (FILIP1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Filamin-A-interacting protein 1 (FILIP1).	[2]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Filamin-A-interacting protein 1 (FILIP1).	[17]

References

• [1] Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy.Nat Genet. 2011 Oct 23;43(12):1247-51. doi: 10.1038/ng.973.
• [2] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [3] De novo microdeletions of chromosome 6q14.1-q14.3 and 6q12.1-q14.1 in two patients with intellectual disability - further delineation of the 6q14 microdeletion syndrome and review of the literature.Eur J Med Genet. 2012 Aug-Sep;55(8-9):490-7. doi: 10.1016/j.ejmg.2012.03.003. Epub 2012 Apr 12.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] 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.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.