Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1BFKPH)

• DOT Name: Rho-related BTB domain-containing protein 3 (RHOBTB3)
• Synonyms: EC 3.6.1.-
• Gene Name: RHOBTB3
• Related Disease: Carcinoma
• UniProt ID: RHBT3_HUMAN
• EC Number: 3.6.1.-
• Pfam ID: PF00651 ; PF00071
• Sequence:
  MSIHIVALGNEGDTFHQDNRPSGLIRTYLGRSPLVSGDESSLLLNAASTVARPVFTEYQA
  SAFGNVKLVVHDCPVWDIFDSDWYTSRNLIGGADIIVIKYNVNDKFSFHEVKDNYIPVIK
  RALNSVPVIIAAVGTRQNEELPCTCPLCTSDRGSCVSTTEGIQLAKELGATYLELHSLDD
  FYIGKYFGGVLEYFMIQALNQKTSEKMKKRKMSNSFHGIRPPQLEQPEKMPVLKAEASHY
  NSDLNNLLFCCQCVDVVFYNPNLKKVVEAHKIVLCAVSHVFMLLFNVKSPTDIQDSSIIR
  TTQDLFAINRDTAFPGASHESSGNPPLRVIVKDALFCSCLSDILRFIYSGAFQWEELEED
  IRKKLKDSGDVSNVIEKVKCILKTPGKINCLRNCKTYQARKPLWFYNTSLKFFLNKPMLA
  DVVFEIQGTTVPAHRAILVARCEVMAAMFNGNYMEAKSVLIPVYGVSKETFLSFLEYLYT
  DSCCPAGIFQAMCLLICAEMYQVSRLQHICELFIITQLQSMPSRELASMNLDIVDLLKKA
  KFHHSDCLSTWLLHFIATNYLIFSQKPEFQDLSVEERSFVEKHRWPSNMYLKQLAEYRKY
  IHSRKCRCLVM
• Function: Rab9-regulated ATPase required for endosome to Golgi transport. Involved in transport vesicle docking at the Golgi complex, possibly by participating in release M6PRBP1/TIP47 from vesicles to permit their efficient docking and fusion at the Golgi. Specifically binds Rab9, but not other Rab proteins. Has low intrinsic ATPase activity due to autoinhibition, which is relieved by Rab9.
• Tissue Specificity: Ubiquitous. Highly expressed in neural and cardiac tissues, pancreas, placenta and testis.
• Reactome Pathway:
  RHOBTB3 ATPase cycle (R-HSA-9706019)
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Rho-related BTB domain-containing protein 3 (RHOBTB3) affects the response to substance of Temozolomide.	[31]
DTI-015	DMXZRW0	Approved	Rho-related BTB domain-containing protein 3 (RHOBTB3) affects the response to substance of DTI-015.	[31]

30 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 Rho-related BTB domain-containing protein 3 (RHOBTB3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[22]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[27]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[29]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho-related BTB domain-containing protein 3 (RHOBTB3).	[26]

References

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• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [10] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] 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.
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• [18] 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.
• [19] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [26] 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.
• [27] 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.
• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [29] 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.
• [30] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [31] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.