Details of Drug Off-Target (DOT)

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

• DOT Name: Intraflagellar transport protein 74 homolog (IFT74)
• Synonyms: Capillary morphogenesis gene 1 protein; CMG-1; Coiled-coil domain-containing protein 2
• Gene Name: IFT74
• Related Disease:
  Bardet-Biedl syndrome 22
  Bardet-Biedl syndrome 20
  Oligospermia
  Schizophrenia
  Bardet biedl syndrome
  Amyotrophic lateral sclerosis
  Spermatogenic failure 58
• UniProt ID: IFT74_HUMAN
• Sequence:
  MASNHKSSAARPVSRGGVGLTGRPPSGIRPLSGNIRVATAMPPGTARPGSRGCPIGTGGV
  LSSQIKVAHRPVTQQGLTGMKTGTKGPQRQILDKSYYLGLLRSKISELTTEVNKLQKGIE
  MYNQENSVYLSYEKRAETLAVEIKELQGQLADYNMLVDKLNTNTEMEEVMNDYNMLKAQN
  DRETQSLDVIFTERQAKEKQIRSVEEEIEQEKQATDDIIKNMSFENQVKYLEMKTTNEKL
  LQELDTLQQQLDSQNMKKESLEAEIAHSQVKQEAVLLHEKLYELESHRDQMIAEDKSIGS
  PMEEREKLLKQIKDDNQEIASMERQLTDTKEKINQFIEEIRQLDMDLEEHQGEMNQKYKE
  LKKREEHMDTFIETFEETKNQELKRKAQIEANIVALLEHCSRNINRIEQISSITNQELKM
  MQDDLNFKSTEVQKSQSTAQNLTSDIQRLQLDLQKMELLESKMTEEQHSLKSKIKQMTTD
  LEIYNDLPALKSSGEEKIKKLHQERMILSTHRNAFKKIMEKQNIEYEALKTQLQENETHS
  QLTNLERKWQHLEQNNFAMKEFIATKSQESDYQPIKKNVTKQIAEYNKTIVDALHSTSGN
• Function: Component of the intraflagellar transport (IFT) complex B: together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. Binds beta-tubulin via its basic region. Required for ciliogenesis. Essential for flagellogenesis during spermatogenesis.
• Tissue Specificity: Highly expressed in adult and fetal kidney and expressed at lower level in adult heart, placenta, lung, liver and pancreas, and in fetal heart, lung and liver. Little to no expression was detected in adult brain and skeletal muscle or in fetal brain, thymus and spleen . Detected in sperm (at protein level) .
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 22	DIS60BR4	Definitive	Autosomal recessive	[1]
Bardet-Biedl syndrome 20	DISXVC6U	Strong	Biomarker	[2]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[5]
Spermatogenic failure 58	DISJQ94R	Limited	Unknown	[6]

15 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 74 homolog (IFT74).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Intraflagellar transport protein 74 homolog (IFT74).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Intraflagellar transport protein 74 homolog (IFT74).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[17]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Intraflagellar transport protein 74 homolog (IFT74).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Intraflagellar transport protein 74 homolog (IFT74).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Intraflagellar transport protein 74 homolog (IFT74).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Intraflagellar transport protein 74 homolog (IFT74).	[20]

References

• [1] Third case of Bardet-Biedl syndrome caused by a biallelic variant predicted to affect splicing of IFT74. Clin Genet. 2021 Jul;100(1):93-99. doi: 10.1111/cge.13962. Epub 2021 Mar 27.
• [2] Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. Am J Hum Genet. 2016 Aug 4;99(2):318-36. doi: 10.1016/j.ajhg.2015.04.023.
• [3] Intraflagellar transport protein 74 is essential for spermatogenesis and male fertility in mice?"Shi L. Huang Q
• [4] Common variants conferring risk of schizophrenia.Nature. 2009 Aug 6;460(7256):744-7. doi: 10.1038/nature08186. Epub 2009 Jul 1.
• [5] Genetic studies of GRN and IFT74 in amyotrophic lateral sclerosis.Neurobiol Aging. 2008 Aug;29(8):1279-82. doi: 10.1016/j.neurobiolaging.2007.02.022. Epub 2007 Mar 23.
• [6] Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. doi: 10.1002/humu.23362. Epub 2017 Nov 6.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] 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.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] 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.
• [15] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [18] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.