Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDR3VBD)

• DOT Name: Intraflagellar transport protein 88 homolog (IFT88)
• Synonyms: Recessive polycystic kidney disease protein Tg737 homolog; Tetratricopeptide repeat protein 10; TPR repeat protein 10
• Gene Name: IFT88
• Related Disease:
  Advanced cancer
  Autosomal dominant polycystic kidney disease
  Liver cancer
  Autosomal recessive polycystic kidney disease
  Carcinoma of liver and intrahepatic biliary tract
  Chondrosarcoma
  Ciliopathy
  Cleft lip/palate
  Cleft palate
  Cystic kidney disease
  Episodic kinesigenic dyskinesia 1
  Gastrointestinal stromal tumour
  Neoplasm
  Polydactyly
  Precancerous condition
  Polycystic kidney disease
  Retinitis pigmentosa
  Isolated cleft palate
  Myeloproliferative neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: IFT88_HUMAN
• Pfam ID: PF12895 ; PF13424 ; PF13432 ; PF13174 ; PF13181
• Sequence:
  MMQNVHLAPETDEDDLYSGYNDYNPIYDIEELENDAAFQQAVRTSHGRRPPITAKISSTA
  VTRPIATGYGSKTSLASSIGRPMTGAIQDGVTRPMTAVRAAGFTKAALRGSAFDPLSQSR
  GPASPLEAKKKDSPEEKIKQLEKEVNELVEESCIANSCGDLKLALEKAKDAGRKERVLVR
  QREQVTTPENINLDLTYSVLFNLASQYSVNEMYAEALNTYQVIVKNKMFSNAGILKMNMG
  NIYLKQRNYSKAIKFYRMALDQVPSVNKQMRIKIMQNIGVTFIQAGQYSDAINSYEHIMS
  MAPNLKAGYNLTICYFAIGDREKMKKAFQKLITVPLEIDEDKYISPSDDPHTNLVTEAIK
  NDHLRQMERERKAMAEKYIMTSAKLIAPVIETSFAAGYDWCVEVVKASQYVELANDLEIN
  KAVTYLRQKDYNQAVEILKVLEKKDSRVKSAAATNLSALYYMGKDFAQASSYADIAVNSD
  RYNPAALTNKGNTVFANGDYEKAAEFYKEALRNDSSCTEALYNIGLTYEKLNRLDEALDC
  FLKLHAILRNSAEVLYQIANIYELMENPSQAIEWLMQVVSVIPTDPQVLSKLGELYDREG
  DKSQAFQYYYESYRYFPCNIEVIEWLGAYYIDTQFWEKAIQYFERASLIQPTQVKWQLMV
  ASCFRRSGNYQKALDTYKDTHRKFPENVECLRFLVRLCTDLGLKDAQEYARKLKRLEKMK
  EIREQRIKSGRDGSGGSRGKREGSASGDSGQNYSASSKGERLSARLRALPGTNEPYESSS
  NKEIDASYVDPLGPQIERPKTAAKKRIDEDDFADEELGDDLLPE
• Function: Positively regulates primary cilium biogenesis. Also involved in autophagy since it is required for trafficking of ATG16L and the expansion of the autophagic compartment.
• Tissue Specificity: Expressed in the heart, brain, liver, lung, kidney, skeletal muscle and pancreas.
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Chaperone Mediated Autophagy (R-HSA-9613829)
  Late endosomal microautophagy (R-HSA-9615710)
  Aggrephagy (R-HSA-9646399)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Autosomal dominant polycystic kidney disease	DISBHWUI	Definitive	Genetic Variation	[2]
Liver cancer	DISDE4BI	Definitive	Biomarker	[3]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[3]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[5]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[6]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[7]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[8]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[9]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[4]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Polydactyly	DIS25BMZ	Strong	Biomarker	[12]
Precancerous condition	DISV06FL	Strong	Biomarker	[13]
Polycystic kidney disease	DISWS3UY	moderate	Biomarker	[14]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[15]
Isolated cleft palate	DISV80CD	Limited	Genetic Variation	[8]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[16]
Thyroid cancer	DIS3VLDH	Limited	Altered Expression	[1]
Thyroid gland carcinoma	DISMNGZ0	Limited	Altered Expression	[1]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[1]

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 Intraflagellar transport protein 88 homolog (IFT88).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Intraflagellar transport protein 88 homolog (IFT88).	[26]

1 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 Intraflagellar transport protein 88 homolog (IFT88).	[23]

References

• [1] Loss-of-function of IFT88 determines metabolic phenotypes in thyroid cancer.Oncogene. 2018 Aug;37(32):4455-4474. doi: 10.1038/s41388-018-0211-6. Epub 2018 May 10.
• [2] New insights into the molecular pathophysiology of polycystic kidney disease.Kidney Int. 1999 Apr;55(4):1187-97. doi: 10.1046/j.1523-1755.1999.00370.x.
• [3] Tg737 acts as a key driver of invasion and migration in liver cancer stem cells and correlates with poor prognosis in patients with hepatocellular carcinoma.Exp Cell Res. 2017 Sep 15;358(2):217-226. doi: 10.1016/j.yexcr.2017.06.021. Epub 2017 Jun 27.
• [4] Primary cilia and signaling pathways in mammalian development, health and disease.Nephron Physiol. 2009;111(3):p39-53. doi: 10.1159/000208212. Epub 2009 Mar 10.
• [5] HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia.Oncol Rep. 2017 Jul;38(1):229-236. doi: 10.3892/or.2017.5694. Epub 2017 Jun 2.
• [6] Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model.Nat Med. 2012 Sep;18(9):1423-8. doi: 10.1038/nm.2860.
• [7] Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate.Hum Mol Genet. 2017 Mar 1;26(5):860-872. doi: 10.1093/hmg/ddx002.
• [8] Association of IFT88 gene variants with nonsyndromic cleft lip with or without cleft palate.Birth Defects Res. 2019 Jul 1;111(11):659-665. doi: 10.1002/bdr2.1504. Epub 2019 Apr 5.
• [9] Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks.Hum Mol Genet. 2009 Jul 1;18(13):2328-43. doi: 10.1093/hmg/ddp165. Epub 2009 Apr 3.
• [10] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [11] Transcriptome profiling identifies a recurrent CRYL1-IFT88 chimeric transcript in hepatocellular carcinoma.Oncotarget. 2017 Jun 20;8(25):40693-40704. doi: 10.18632/oncotarget.17244.
• [12] Dynll1 is essential for development and promotes endochondral bone formation by regulating intraflagellar dynein function in primary cilia.Hum Mol Genet. 2019 Aug 1;28(15):2573-2588. doi: 10.1093/hmg/ddz083.
• [13] The tetratricopeptide repeat containing Tg737 gene is a liver neoplasia tumor suppressor gene.Oncogene. 1997 Oct 9;15(15):1797-803. doi: 10.1038/sj.onc.1201535.
• [14] Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella.J Cell Biol. 2000 Oct 30;151(3):709-18. doi: 10.1083/jcb.151.3.709.
• [15] IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. Hum Genet. 2018 Jul;137(6-7):447-458. doi: 10.1007/s00439-018-1897-9. Epub 2018 Jul 5.
• [16] Centrosome-kinase fusions promote oncogenic signaling and disrupt centrosome function in myeloproliferative neoplasms.PLoS One. 2014 Mar 21;9(3):e92641. doi: 10.1371/journal.pone.0092641. eCollection 2014.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [23] 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.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [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.