Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6ZOWMU)

• DOT Name: Sorting nexin-5 (SNX5)
• Gene Name: SNX5
• Related Disease:
  Advanced cancer
  Chikungunya virus infection
  Differentiated thyroid carcinoma
  Fanconi anemia complementation group A
  Gastric cancer
  Gastric neoplasm
  Goiter
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  High blood pressure
  Hyperinsulinemia
  Thyroid cancer
  Thyroid gland carcinoma
  Head-neck squamous cell carcinoma
  Neoplasm
  Thyroid tumor
  Thyroid gland papillary carcinoma
• UniProt ID: SNX5_HUMAN
• PDB ID: 1SYS; 5TGH; 5TGI; 5TGJ; 5WY2; 6N5X; 6N5Y; 6N5Z; 8A1G; 8ABQ; 8AFZ
• Pfam ID: PF00787 ; PF09325
• Sequence:
  MAAVPELLQQQEEDRSKLRSVSVDLNVDPSLQIDIPDALSERDKVKFTVHTKTTLPTFQS
  PEFSVTRQHEDFVWLHDTLIETTDYAGLIIPPAPTKPDFDGPREKMQKLGEGEGSMTKEE
  FAKMKQELEAEYLAVFKKTVSSHEVFLQRLSSHPVLSKDRNFHVFLEYDQDLSVRRKNTK
  EMFGGFFKSVVKSADEVLFTGVKEVDDFFEQEKNFLINYYNRIKDSCVKADKMTRSHKNV
  ADDYIHTAACLHSLALEEPTVIKKYLLKVAELFEKLRKVEGRVSSDEDLKLTELLRYYML
  NIEAAKDLLYRRTKALIDYENSNKALDKARLKSKDVKLAEAHQQECCQKFEQLSESAKEE
  LINFKRKRVAAFRKNLIEMSELEIKHARNNVSLLQSCIDLFKNN
• Function: Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Does not have in vitro vesicle-to-membrane remodeling activity. Involved in retrograde transport of lysosomal enzyme receptor IGF2R. May function as link between endosomal transport vesicles and dynactin (Probable). Plays a role in the internalization of EGFR after EGF stimulation (Probable). Involved in EGFR endosomal sorting and degradation; the function involves PIP5K1C isoform 3 and is retromer-independent. Together with PIP5K1C isoform 3 facilitates HGS interaction with ubiquitinated EGFR, which initiates EGFR sorting to intraluminal vesicles (ILVs) of the multivesicular body for subsequent lysosomal degradation (Probable). Involved in E-cadherin sorting and degradation; inhibits PIP5K1C isoform 3-mediated E-cadherin degradation. Plays a role in macropinocytosis.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway: Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[2]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Altered Expression	[3]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[4]
Goiter	DISLCGI6	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[4]
High blood pressure	DISY2OHH	Strong	Altered Expression	[6]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[6]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[3]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[3]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sorting nexin-5 (SNX5).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sorting nexin-5 (SNX5).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorting nexin-5 (SNX5).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Sorting nexin-5 (SNX5).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Sorting nexin-5 (SNX5).	[13]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Sorting nexin-5 (SNX5).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sorting nexin-5 (SNX5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sorting nexin-5 (SNX5).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sorting nexin-5 (SNX5).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sorting nexin-5 (SNX5).	[18]

References

• [1] SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein.Biochem Biophys Res Commun. 1999 Nov 30;265(3):630-5. doi: 10.1006/bbrc.1999.1731.
• [2] Comparative Characterization of the Sindbis Virus Proteome from Mammalian and Invertebrate Hosts Identifies nsP2 as a Component of the Virion and Sorting Nexin 5 as a Significant Host Factor for Alphavirus Replication.J Virol. 2018 Jun 29;92(14):e00694-18. doi: 10.1128/JVI.00694-18. Print 2018 Jul 15.
• [3] Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression.J Pathol. 2017 Nov;243(3):342-353. doi: 10.1002/path.4951.
• [4] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [5] Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway.Oncogene. 2020 Mar;39(10):2140-2155. doi: 10.1038/s41388-019-1131-9. Epub 2019 Dec 9.
• [6] Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice.Diabetologia. 2018 Mar;61(3):727-737. doi: 10.1007/s00125-017-4482-1. Epub 2017 Oct 28.
• [7] Sorting Nexin 5 Controls Head and Neck Squamous Cell Carcinoma Progression by Modulating FBW7.J Cancer. 2019 Jun 2;10(13):2942-2952. doi: 10.7150/jca.31055. eCollection 2019.
• [8] Sorting nexin 5 of a new diagnostic marker of papillary thyroid carcinoma regulates Caspase-2.Cancer Sci. 2012 Jul;103(7):1356-62. doi: 10.1111/j.1349-7006.2012.02296.x. Epub 2012 Jun 4.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [15] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] 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.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.