Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXYC20V)

• DOT Name: Intraflagellar transport protein 57 homolog (IFT57)
• Synonyms: Dermal papilla-derived protein 8; Estrogen-related receptor beta-like protein 1; HIP1-interacting protein; MHS4R2
• Gene Name: IFT57
• Related Disease:
  Ciliopathy
  Glioblastoma multiforme
  Huntington disease
  Orofaciodigital syndrome
  Orofaciodigital syndrome I
  Orofaciodigital syndrome 18
• UniProt ID: IFT57_HUMAN
• Pfam ID: PF10498
• Sequence:
  MTAALAVVTTSGLEDGVPRSRGEGTGEVVLERGPGAAYHMFVVMEDLVEKLKLLRYEEEF
  LRKSNLKAPSRHYFALPTNPGEQFYMFCTLAAWLINKAGRPFEQPQEYDDPNATISNILS
  ELRSFGRTADFPPSKLKSGYGEHVCYVLDCFAEEALKYIGFTWKRPIYPVEELEEESVAE
  DDAELTLNKVDEEFVEEETDNEENFIDLNVLKAQTYHLDMNETAKQEDILESTTDAAEWS
  LEVERVLPQLKVTIRTDNKDWRIHVDQMHQHRSGIESALKETKGFLDKLHNEITRTLEKI
  SSREKYINNQLENLVQEYRAAQAQLSEAKERYQQGNGGVTERTRLLSEVMEELEKVKQEM
  EEKGSSMTDGAPLVKIKQSLTKLKQETVEMDIRIGIVEHTLLQSKLKEKSNMTRNMHATV
  IPEPATGFY
• Function: Required for the formation of cilia. Plays an indirect role in sonic hedgehog signaling, cilia being required for all activity of the hedgehog pathway. Has pro-apoptotic function via its interaction with HIP1, leading to recruit caspase-8 (CASP8) and trigger apoptosis. Has the ability to bind DNA sequence motif 5'-AAAGACATG-3' present in the promoter of caspase genes such as CASP1, CASP8 and CASP10, suggesting that it may act as a transcription regulator; however the relevance of such function remains unclear.
• Tissue Specificity: Present in many tissues such as brain, thymus, lymph node, lung, liver, skin and kidney (at protein level).
• KEGG Pathway:
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Huntington disease	DISQPLA4	Strong	Biomarker	[3]
Orofaciodigital syndrome	DISSB296	Strong	Biomarker	[1]
Orofaciodigital syndrome I	DIST27XL	Strong	Biomarker	[1]
Orofaciodigital syndrome 18	DISLT8VU	Limited	Unknown	[4]

11 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 Intraflagellar transport protein 57 homolog (IFT57).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Intraflagellar transport protein 57 homolog (IFT57).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Intraflagellar transport protein 57 homolog (IFT57).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Intraflagellar transport protein 57 homolog (IFT57).	[6]

References

• [1] Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia.Clin Genet. 2016 Dec;90(6):509-517. doi: 10.1111/cge.12785. Epub 2016 Apr 29.
• [2] BLOC1S2 interacts with the HIPPI protein and sensitizes NCH89 glioblastoma cells to apoptosis.Apoptosis. 2008 Mar;13(3):437-47. doi: 10.1007/s10495-007-0176-3.
• [3] Regulation of RE1 protein silencing transcription factor (REST) expression by HIP1 protein interactor (HIPPI).J Biol Chem. 2011 Sep 30;286(39):33759-69. doi: 10.1074/jbc.M111.265173. Epub 2011 Aug 6.
• [4] Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries. Int J Cardiol. 2016 Feb 1;204:115-21. doi: 10.1016/j.ijcard.2015.11.127. Epub 2015 Nov 22.
• [5] 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.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [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] 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.
• [13] 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.
• [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] 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.