Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCQ7UDS)

• DOT Name: Inactive rhomboid protein 1 (RHBDF1)
• Synonyms: iRhom1; Epidermal growth factor receptor-related protein; Rhomboid 5 homolog 1; Rhomboid family member 1; p100hRho
• Gene Name: RHBDF1
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Cardiac arrest
  Central nervous system neoplasm
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Familial adenomatous polyposis
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Pancreatic cancer
  Stomach cancer
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
  Fibrosarcoma
  Head and neck cancer
  Head and neck carcinoma
  Hemoglobinopathy
  Invasive ductal breast carcinoma
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: RHDF1_HUMAN
• Pfam ID: PF12595 ; PF01694
• Sequence:
  MSEARRDSTSSLQRKKPPWLKLDIPSAVPLTAEEPSFLQPLRRQAFLRSVSMPAETAHIS
  SPHHELRRPVLQRQTSITQTIRRGTADWFGVSKDSDSTQKWQRKSIRHCSQRYGKLKPQV
  LRELDLPSQDNVSLTSTETPPPLYVGPCQLGMQKIIDPLARGRAFRVADDTAEGLSAPHT
  PVTPGAASLCSFSSSRSGFHRLPRRRKRESVAKMSFRAAAALMKGRSVRDGTFRRAQRRS
  FTPASFLEEDTTDFPDELDTSFFAREGILHEELSTYPDEVFESPSEAALKDWEKAPEQAD
  LTGGALDRSELERSHLMLPLERGWRKQKEGAAAPQPKVRLRQEVVSTAGPRRGQRIAVPV
  RKLFAREKRPYGLGMVGRLTNRTYRKRIDSFVKRQIEDMDDHRPFFTYWLTFVHSLVTIL
  AVCIYGIAPVGFSQHETVDSVLRNRGVYENVKYVQQENFWIGPSSEALIHLGAKFSPCMR
  QDPQVHSFIRSAREREKHSACCVRNDRSGCVQTSEEECSSTLAVWVKWPIHPSAPELAGH
  KRQFGSVCHQDPRVCDEPSSEDPHEWPEDITKWPICTKNSAGNHTNHPHMDCVITGRPCC
  IGTKGRCEITSREYCDFMRGYFHEEATLCSQVHCMDDVCGLLPFLNPEVPDQFYRLWLSL
  FLHAGILHCLVSICFQMTVLRDLEKLAGWHRIAIIYLLSGVTGNLASAIFLPYRAEVGPA
  GSQFGILACLFVELFQSWQILARPWRAFFKLLAVVLFLFTFGLLPWIDNFAHISGFISGL
  FLSFAFLPYISFGKFDLYRKRCQIIIFQVVFLGLLAGLVVLFYVYPVRCEWCEFLTCIPF
  TDKFCEKYELDAQLH
• Function: Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation. Does not exhibit any protease activity on its own.
• Tissue Specificity: Highly expressed in cerebellum, cerebrum, heart, skeletal muscle, placenta, pancreatic islet and testis. Detected at lower levels in colon, kidney, small intestine and lung.
• KEGG Pathway: TNF sig.ling pathway (hsa04668)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[1]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[3]
Glioma	DIS5RPEH	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Pancreatic cancer	DISJC981	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[9]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[9]
Fibrosarcoma	DISWX7MU	Limited	Altered Expression	[10]
Head and neck cancer	DISBPSQZ	Limited	Altered Expression	[11]
Head and neck carcinoma	DISOU1DS	Limited	Altered Expression	[11]
Hemoglobinopathy	DISCT4GX	Limited	Genetic Variation	[12]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[11]

3 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 Inactive rhomboid protein 1 (RHBDF1).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Inactive rhomboid protein 1 (RHBDF1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Inactive rhomboid protein 1 (RHBDF1).	[27]

20 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 Inactive rhomboid protein 1 (RHBDF1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[19]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[21]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[23]
Estrone	DM5T6US	Approved	Estrone decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[21]
Mestranol	DMG3F94	Approved	Mestranol decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inactive rhomboid protein 1 (RHBDF1).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Inactive rhomboid protein 1 (RHBDF1).	[19]

References

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• [3] Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.Nat Genet. 2017 May;49(5):789-794. doi: 10.1038/ng.3823. Epub 2017 Mar 27.
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• [5] RHBDF1 regulates APC-mediated stimulation of the epithelial-to-mesenchymal transition and proliferation of colorectal cancer cells in part via the Wnt/-catenin signalling pathway.Exp Cell Res. 2018 Jul 1;368(1):24-36. doi: 10.1016/j.yexcr.2018.04.009. Epub 2018 Apr 11.
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• [10] Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17.Sci Signal. 2015 Nov 3;8(401):ra109. doi: 10.1126/scisignal.aac5356.
• [11] Human rhomboid family-1 gene silencing causes apoptosis or autophagy to epithelial cancer cells and inhibits xenograft tumor growth.Mol Cancer Ther. 2008 Jun;7(6):1355-64. doi: 10.1158/1535-7163.MCT-08-0104. Epub 2008 Jun 4.
• [12] Construction and expression of a recombinant adeno-associated virus that harbors a human beta-globin-encoding cDNA.Gene. 1991 Aug 15;104(2):253-7. doi: 10.1016/0378-1119(91)90258-d.
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• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
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• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [21] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [26] 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.
• [27] 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.
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• [29] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [30] 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.