Details of Drug Off-Target (DOT)

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

• DOT Name: Intraflagellar transport protein 46 homolog (IFT46)
• Gene Name: IFT46
• Related Disease: Beckwith-Wiedemann syndrome
• UniProt ID: IFT46_HUMAN
• Pfam ID: PF12317
• Sequence:
  MADNSSDECEEENNKEKKKTSQLTPQRGFSENEDDDDDDDDSSETDSDSDDDDEEHGAPL
  EGAYDPADYEHLPVSAEIKELFQYISRYTPQLIDLDHKLKPFIPDFIPAVGDIDAFLKVP
  RPDGKPDNLGLLVLDEPSTKQSDPTVLSLWLTENSKQHNITQHMKVKSLEDAEKNPKAID
  TWIESISELHRSKPPATVHYTRPMPDIDTLMQEWSPEFEELLGKVSLPTAEIDCSLAEYI
  DMICAILDIPVYKSRIQSLHLLFSLYSEFKNSQHFKALAEGKKAFTPSSNSTSQAGDMET
  LTFS
• Function: Forms part of a complex involved in intraflagellar transport (IFT), the bi-directional movement of particles required for the assembly, maintenance and functioning of primary cilia. May play a role in chondrocyte maturation and skeletogenesis.
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Biomarker	[1]

7 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 46 homolog (IFT46).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Intraflagellar transport protein 46 homolog (IFT46).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Intraflagellar transport protein 46 homolog (IFT46).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Intraflagellar transport protein 46 homolog (IFT46).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intraflagellar transport protein 46 homolog (IFT46).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Intraflagellar transport protein 46 homolog (IFT46).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Intraflagellar transport protein 46 homolog (IFT46).	[10]

2 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 46 homolog (IFT46).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Intraflagellar transport protein 46 homolog (IFT46).	[8]

References

• [1] C11orf21, a novel gene within the Beckwith-Wiedemann syndrome region in human chromosome 11p15.5.Gene. 2000 Oct 3;256(1-2):311-7. doi: 10.1016/s0378-1119(00)00377-2.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.