Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTROM7N3)

• DOT Name: FH1/FH2 domain-containing protein 1 (FHOD1)
• Synonyms: Formin homolog overexpressed in spleen 1; FHOS; Formin homology 2 domain-containing protein 1
• Gene Name: FHOD1
• Related Disease:
  Breast cancer
  Triple negative breast cancer
  Breast carcinoma
  Melanoma
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: FHOD1_HUMAN
• PDB ID: 3DAD; 6XF1; 6XF2
• Pfam ID: PF02181 ; PF18382
• Sequence:
  MAGGEDRGDGEPVSVVTVRVQYLEDTDPFACANFPEPRRAPTCSLDGALPLGAQIPAVHR
  LLGAPLKLEDCALQVSPSGYYLDTELSLEEQREMLEGFYEEISKGRKPTLILRTQLSVRV
  NAILEKLYSSSGPELRRSLFSLKQIFQEDKDLVPEFVHSEGLSCLIRVGAAADHNYQSYI
  LRALGQLMLFVDGMLGVVAHSDTIQWLYTLCASLSRLVVKTALKLLLVFVEYSENNAPLF
  IRAVNSVASTTGAPPWANLVSILEEKNGADPELLVYTVTLINKTLAALPDQDSFYDVTDA
  LEQQGMEALVQRHLGTAGTDVDLRTQLVLYENALKLEDGDIEEAPGAGGRRERRKPSSEE
  GKRSRRSLEGGGCPARAPEPGPTGPASPVGPTSSTGPALLTGPASSPVGPPSGLQASVNL
  FPTISVAPSADTSSERSIYKARFLENVAAAETEKQVALAQGRAETLAGAMPNEAGGHPDA
  RQLWDSPETAPAARTPQSPAPCVLLRAQRSLAPEPKEPLIPASPKAEPIWELPTRAPRLS
  IGDLDFSDLGEDEDQDMLNVESVEAGKDIPAPSPPLPLLSGVPPPPPLPPPPPIKGPFPP
  PPPLPLAAPLPHSVPDSSALPTKRKTVKLFWRELKLAGGHGVSASRFGPCATLWASLDPV
  SVDTARLEHLFESRAKEVLPSKKAGEGRRTMTTVLDPKRSNAINIGLTTLPPVHVIKAAL
  LNFDEFAVSKDGIEKLLTMMPTEEERQKIEEAQLANPDIPLGPAENFLMTLASIGGLAAR
  LQLWAFKLDYDSMEREIAEPLFDLKVGMEQLVQNATFRCILATLLAVGNFLNGSQSSGFE
  LSYLEKVSEVKDTVRRQSLLHHLCSLVLQTRPESSDLYSEIPALTRCAKVDFEQLTENLG
  QLERRSRAAEESLRSLAKHELAPALRARLTHFLDQCARRVAMLRIVHRRVCNRFHAFLLY
  LGYTPQAAREVRIMQFCHTLREFALEYRTCRERVLQQQQKQATYRERNKTRGRMITETEK
  FSGVAGEAPSNPSVPVAVSSGPGRGDADSHASMKSLLTSRPEDTTHNRRSRGMVQSSSPI
  MPTVGPSTASPEEPPGSSLPSDTSDEIMDLLVQSVTKSSPRALAARERKRSRGNRKSLRR
  TLKSGLGDDLVQALGLSKGPGLEV
• Function: Required for the assembly of F-actin structures, such as stress fibers. Depends on the Rho-ROCK cascade for its activity. Contributes to the coordination of microtubules with actin fibers and plays a role in cell elongation. Acts synergistically with ROCK1 to promote SRC-dependent non-apoptotic plasma membrane blebbing.
• Tissue Specificity: Ubiquitous. Highly expressed in spleen.
• KEGG Pathway: Salmonella infection (hsa05132)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[2]
Melanoma	DIS1RRCY	Limited	Altered Expression	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[2]

9 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 FH1/FH2 domain-containing protein 1 (FHOD1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[8]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FH1/FH2 domain-containing protein 1 (FHOD1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of FH1/FH2 domain-containing protein 1 (FHOD1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of FH1/FH2 domain-containing protein 1 (FHOD1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of FH1/FH2 domain-containing protein 1 (FHOD1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of FH1/FH2 domain-containing protein 1 (FHOD1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of FH1/FH2 domain-containing protein 1 (FHOD1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of FH1/FH2 domain-containing protein 1 (FHOD1).	[15]

References

• [1] Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities.Breast Cancer (Auckl). 2018 Aug 24;12:1178223418792247. doi: 10.1177/1178223418792247. eCollection 2018.
• [2] FHOD1 formin is upregulated in melanomas and modifies proliferation and tumor growth.Exp Cell Res. 2017 Jan 1;350(1):267-278. doi: 10.1016/j.yexcr.2016.12.004. Epub 2016 Dec 2.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] 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.
• [9] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] 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.
• [15] 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.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.