Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSJ5KKA)

• DOT Name: Formin-binding protein 1 (FNBP1)
• Synonyms: Formin-binding protein 17; hFBP17
• Gene Name: FNBP1
• Related Disease:
  Ankylosing spondylitis
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Juvenile idiopathic arthritis
  Psoriasis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  Type-1 diabetes
  Ulcerative colitis
  Acute myelogenous leukaemia
• UniProt ID: FNBP1_HUMAN
• PDB ID: 2EFL
• Pfam ID: PF00611 ; PF00018
• Sequence:
  MSWGTELWDQFDNLEKHTQWGIDILEKYIKFVKERTEIELSYAKQLRNLSKKYQPKKNSK
  EEEEYKYTSCKAFISNLNEMNDYAGQHEVISENMASQIIVDLARYVQELKQERKSNFHDG
  RKAQQHIETCWKQLESSKRRFERDCKEADRAQQYFEKMDADINVTKADVEKARQQAQIRH
  QMAEDSKADYSSILQKFNHEQHEYYHTHIPNIFQKIQEMEERRIVRMGESMKTYAEVDRQ
  VIPIIGKCLDGIVKAAESIDQKNDSQLVIEAYKSGFEPPGDIEFEDYTQPMKRTVSDNSL
  SNSRGEGKPDLKFGGKSKGKLWPFIKKNKLMSLLTSPHQPPPPPPASASPSAVPNGPQSP
  KQQKEPLSHRFNEFMTSKPKIHCFRSLKRGLSLKLGATPEDFSNLPPEQRRKKLQQKVDE
  LNKEIQKEMDQRDAITKMKDVYLKNPQMGDPASLDHKLAEVSQNIEKLRVETQKFEAWLA
  EVEGRLPARSEQARRQSGLYDSQNPPTVNNCAQDRESPDGSYTEEQSQESEMKVLATDFD
  DEFDDEEPLPAIGTCKALYTFEGQNEGTISVVEGETLYVIEEDKGDGWTRIRRNEDEEGY
  VPTSYVEVCLDKNAKDS
• Function: May act as a link between RND2 signaling and regulation of the actin cytoskeleton. Required to coordinate membrane tubulation with reorganization of the actin cytoskeleton during the late stage of clathrin-mediated endocytosis. Binds to lipids such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine and promotes membrane invagination and the formation of tubules. Also enhances actin polymerization via the recruitment of WASL/N-WASP, which in turn activates the Arp2/3 complex. Actin polymerization may promote the fission of membrane tubules to form endocytic vesicles. May be required for the lysosomal retention of FASLG/FASL.
• Tissue Specificity: Very highly expressed in the epithelial cells of the gastrointestinal tract, respiratory, reproductive and urinary systems. Also highly expressed in brown adipose tissue, cardiomyocytes, enteric ganglia and glucagon producing cells of the pancreas. Expressed in germ cells of the testis and all regions of the brain.
• KEGG Pathway: Shigellosis (hsa05131)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOJ GTPase cycle (R-HSA-9013409)
  RND2 GTPase cycle (R-HSA-9696270)
  Clathrin-mediated endocytosis (R-HSA-8856828)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ankylosing spondylitis	DISRC6IR	moderate	Genetic Variation	[1]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[1]
Autoimmune disease, susceptibility to, 6	DISHNUXI	moderate	Genetic Variation	[1]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[1]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[1]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[1]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[1]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Genetic Variation	[1]
Psoriasis	DIS59VMN	moderate	Genetic Variation	[1]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	moderate	Genetic Variation	[1]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[1]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[1]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Formin-binding protein 1 (FNBP1) affects the response to substance of Methotrexate.	[20]
Fluorouracil	DMUM7HZ	Approved	Formin-binding protein 1 (FNBP1) affects the response to substance of Fluorouracil.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Formin-binding protein 1 (FNBP1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Formin-binding protein 1 (FNBP1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Formin-binding protein 1 (FNBP1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Formin-binding protein 1 (FNBP1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Formin-binding protein 1 (FNBP1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Formin-binding protein 1 (FNBP1).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Formin-binding protein 1 (FNBP1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Formin-binding protein 1 (FNBP1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Formin-binding protein 1 (FNBP1).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Formin-binding protein 1 (FNBP1).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Formin-binding protein 1 (FNBP1).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Formin-binding protein 1 (FNBP1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Formin-binding protein 1 (FNBP1).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Formin-binding protein 1 (FNBP1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Formin-binding protein 1 (FNBP1).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Formin-binding protein 1 (FNBP1).	[17]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Formin-binding protein 1 (FNBP1).	[18]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Formin-binding protein 1 (FNBP1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Formin-binding protein 1 (FNBP1).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Formin-binding protein 1 (FNBP1).	[9]

References

• [1] Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
• [2] Identification of a novel RAS GTPase-activating protein (RASGAP) gene at 9q34 as an MLL fusion partner in a patient with de novo acute myeloid leukemia.Genes Chromosomes Cancer. 2004 Apr;39(4):324-34. doi: 10.1002/gcc.20004.
• [3] 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.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [8] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [9] 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.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [19] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.