Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXB13E6)

• DOT Name: Protein inturned (INTU)
• Synonyms: Inturned planar cell polarity effector homolog; PDZ domain-containing protein 6
• Gene Name: INTU
• Related Disease:
  Neoplasm
  Primary biliary cholangitis
  Adenocarcinoma
  Ataxia-telangiectasia
  Breast cancer
  Breast carcinoma
  Bronchopulmonary dysplasia
  Carpal tunnel syndrome
  Cholangiocarcinoma
  Diabetic kidney disease
  Diabetic retinopathy
  Endometriosis
  Fatty liver disease
  Herpes simplex infection
  Hyperglycemia
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Non-insulin dependent diabetes
  Obesity
  Orofaciodigital syndrome type 6
  Polycythemia vera
  Rectal carcinoma
  Renal fibrosis
  Subarachnoid hemorrhage
  Hepatocellular carcinoma
  Orofaciodigital syndrome 17
  Glioma
  Atrial septal defect
  Autism spectrum disorder
  Escherichia coli infection
  Hereditary hemochromatosis
  Metastatic melanoma
  Short-rib thoracic dysplasia 20 with polydactyly
  Stroke
  Type-1/2 diabetes
• UniProt ID: INTU_HUMAN
• PDB ID: 7Q3D
• Pfam ID: PF19031 ; PF19032 ; PF19033
• Sequence:
  MASVASCDSRPSSDELPGDPSSQEEDEDYDFEDRVSDSGSYSSASSDYDDLEPEWLDSVQ
  KNGELFYLELSEDEEESLLPETPTVNHVRFSENEIIIEDDYKERKKYEPKLKQFTKILRR
  KRLLPKRCNKKNSNDNGPVSILKHQSNQKTGVIVQQRYKDVNVYVNPKKLTVIKAKEQLK
  LLEVLVGIIHQTKWSWRRTGKQGDGERLVVHGLLPGGSAMKSGQVLIGDVLVAVNDVDVT
  TENIERVLSCIPGPMQVKLTFENAYDVKRETSHPRQKKTQSNTSDLVKLLWGEEVEGIQQ
  SGLNTPHIIMYLTLQLDSETSKEEQEILYHYPMSEASQKLKSVRGIFLTLCDMLENVTGT
  QVTSSSLLLNGKQIHVAYWKESDKLLLIGLPAEEVPLPRLRNMIENVIQTLKFMYGSLDS
  AFCQIENVPRLDHFFNLFFQRALQPAKLHSSASPSAQQYDASSAVLLDNLPGVRWLTLPL
  EIKMELDMALSDLEAADFAELSEDYYDMRRLYTILGSSLFYKGYLICSHLPKDDLIDIAV
  YCRHYCLLPLAAKQRIGQLIIWREVFPQHHLRPLADSSTEVFPEPEGRYFLLVVGLKHYM
  LCVLLEAGGCASKAIGSPGPDCVYVDQVKTTLHQLDGVDSRIDERLASSPVPCLSCADWF
  LTGSREKTDSLTTSPILSRLQGTSKVATSPTCRRTLFGDYSLKTRKPSPSCSSGGSDNGC
  EGGEDDGFSPHTTPDAVRKQRESQGSDGLEESGTLLKVTKKKSTLPNPFHLGNLKKDLPE
  KELEIYNTVKLTSGPENTLFHYVALETVQGIFITPTLEEVAQLSGSIHPQLIKNFHQCCL
  SIRAVFQQTLVEEKKKGLNSGDHSDSAKSVSSLNPVKEHGVLFECSPGNWTDQKKAPPVM
  AYWVVGRLFLHPKPQELYVCFHDSVTEIAIEIAFKLFFGLTL
• Function: Plays a key role in ciliogenesis and embryonic development. Regulator of cilia formation by controlling the organization of the apical actin cytoskeleton and the positioning of the basal bodies at the apical cell surface, which in turn is essential for the normal orientation of elongating ciliary microtubules. Plays a key role in definition of cell polarity via its role in ciliogenesis but not via conversion extension. Has an indirect effect on hedgehog signaling. Proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies.
• Reactome Pathway: Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[6]
Carpal tunnel syndrome	DISHQ3BE	Strong	Biomarker	[7]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[8]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[9]
Diabetic retinopathy	DISHGUJM	Strong	Altered Expression	[10]
Endometriosis	DISX1AG8	Strong	Biomarker	[11]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[12]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[13]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[14]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[15]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[12]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[16]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Orofaciodigital syndrome type 6	DISQY7K4	Strong	Biomarker	[17]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[18]
Rectal carcinoma	DIS8FRR7	Strong	Genetic Variation	[19]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[9]
Subarachnoid hemorrhage	DISI7I8Y	Strong	Biomarker	[20]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[21]
Orofaciodigital syndrome 17	DISFIZVE	Moderate	Autosomal recessive	[22]
Glioma	DIS5RPEH	Disputed	Biomarker	[23]
Atrial septal defect	DISJT76B	Limited	Biomarker	[24]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[24]
Escherichia coli infection	DISPP65M	Limited	Altered Expression	[25]
Hereditary hemochromatosis	DISVG5MT	Limited	Altered Expression	[26]
Metastatic melanoma	DISSL43L	Limited	Genetic Variation	[27]
Short-rib thoracic dysplasia 20 with polydactyly	DISHHBGD	Limited	Unknown	[28]
Stroke	DISX6UHX	Limited	Genetic Variation	[29]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein inturned (INTU).	[30]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein inturned (INTU).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein inturned (INTU).	[32]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein inturned (INTU).	[33]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein inturned (INTU).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein inturned (INTU).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein inturned (INTU).	[36]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Protein inturned (INTU).	[33]

References

• [1] Phenolic Composition and Bioactivity of Lavandula pedunculata (Mill.) Cav. Samples from Different Geographical Origin.Molecules. 2018 Apr 28;23(5):1037. doi: 10.3390/molecules23051037.
• [2] Semisynthetic bile acids: a new therapeutic option for metabolic syndrome.Pharmacol Res. 2019 Aug;146:104333. doi: 10.1016/j.phrs.2019.104333. Epub 2019 Jun 26.
• [3] Mouse mammary tumor virus sequences responsible for activating cellular oncogenes.J Virol. 1998 Dec;72(12):9428-35. doi: 10.1128/JVI.72.12.9428-9435.1998.
• [4] Modulation of radiation-induced chromosomal damage by inhibitors of DNA repair and flow cytometric analysis in ataxia telangiectasia cells with 'intermediate radiosensitivity'.Mutagenesis. 1995 Nov;10(6):523-9. doi: 10.1093/mutage/10.6.523.
• [5] Identification of breast cancer-restricted antigens by antibody screening of SKBR3 cDNA library using a preselected patient's serum.Breast Cancer Res Treat. 2002 Jun;73(3):245-56. doi: 10.1023/a:1015854415746.
• [6] Neurocognitive impairment in unaffected siblings of youth with bipolar disorder.Psychol Med. 2009 Aug;39(8):1253-63. doi: 10.1017/S0033291708004832. Epub 2008 Dec 11.
• [7] Electrophysiological Assessment for Splinting in the Treatment of Carpal Tunnel Syndrome.Neurol Med Chir (Tokyo). 2017 Sep 15;57(9):472-480. doi: 10.2176/nmc.oa.2017-0075. Epub 2017 Jul 28.
• [8] The expression of arginase-1, keratin (K) 8 and K18 in combined hepatocellular-cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell type.J Clin Pathol. 2016 Oct;69(10):846-51. doi: 10.1136/jclinpath-2015-203491. Epub 2016 Mar 11.
• [9] FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. J Am Soc Nephrol. 2018 Jan;29(1):118-137.
• [10] Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice.Diabetes. 2018 Sep;67(9):1867-1879. doi: 10.2337/db18-0158. Epub 2018 Apr 30.
• [11] TGR5 agonist INT-777 mitigates inflammatory response in human endometriotic stromal cells: A therapeutic implication for endometriosis.Int Immunopharmacol. 2019 Jun;71:93-99. doi: 10.1016/j.intimp.2019.02.044. Epub 2019 Mar 14.
• [12] INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis.World J Gastroenterol. 2018 Jan 14;24(2):195-210. doi: 10.3748/wjg.v24.i2.195.
• [13] Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses.Front Immunol. 2018 Oct 2;9:2289. doi: 10.3389/fimmu.2018.02289. eCollection 2018.
• [14] Community groups or mobile phone messaging to prevent and control type 2 diabetes and intermediate hyperglycaemia in Bangladesh (DMagic): a cluster-randomised controlled trial.Lancet Diabetes Endocrinol. 2019 Mar;7(3):200-212. doi: 10.1016/S2213-8587(19)30001-4. Epub 2019 Feb 4.
• [15] Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.Mol Metab. 2018 Mar;9:131-140. doi: 10.1016/j.molmet.2018.01.005. Epub 2018 Jan 11.
• [16] A low-calorie diet with or without interval exercise training improves adiposopathy in obese women.Appl Physiol Nutr Metab. 2019 Oct;44(10):1057-1064. doi: 10.1139/apnm-2018-0717. Epub 2019 Feb 20.
• [17] INTU-related oral-facial-digital syndrome type VI: A confirmatory report.Clin Genet. 2018 Jun;93(6):1205-1209. doi: 10.1111/cge.13238. Epub 2018 Apr 6.
• [18] Selection of cellular genetic markers for the detection of infectious poliovirus.J Appl Microbiol. 2018 Apr;124(4):1001-1007. doi: 10.1111/jam.13621. Epub 2018 Jan 11.
• [19] Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation.Clin Cancer Res. 2015 Apr 1;21(7):1583-90. doi: 10.1158/1078-0432.CCR-14-0857. Epub 2015 Jan 14.
• [20] Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKC/ALDH2 pathway after subarachnoid hemorrhage in rats.Free Radic Biol Med. 2019 Nov 1;143:441-453. doi: 10.1016/j.freeradbiomed.2019.09.002. Epub 2019 Sep 4.
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• [26] INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma.Oncogene. 2017 Aug 31;36(35):4997-5005. doi: 10.1038/onc.2017.117. Epub 2017 May 1.
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• [32] 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.
• [33] 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.
• [34] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [35] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.