Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLNQ0ZM)

• DOT Name: Sorting nexin-9 (SNX9)
• Synonyms: SH3 and PX domain-containing protein 1; Protein SDP1; SH3 and PX domain-containing protein 3A
• Gene Name: SNX9
• Related Disease:
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Alzheimer disease
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Focal segmental glomerulosclerosis
  Hyperinsulinemia
  Neoplasm
  Nephropathy
  Oculocerebrorenal syndrome
  Pulmonary fibrosis
  Colorectal carcinoma
  Acute myelogenous leukaemia
• UniProt ID: SNX9_HUMAN
• PDB ID: 2RAI; 2RAJ; 2RAK; 3DYT; 3DYU; 3LGE; 7OJ9
• Pfam ID: PF10456 ; PF00787 ; PF07653
• Sequence:
  MATKARVMYDFAAEPGNNELTVNEGEIITITNPDVGGGWLEGRNIKGERGLVPTDYVEIL
  PSDGKDQFSCGNSVADQAFLDSLSASTAQASSSAASNNHQVGSGNDPWSAWSASKSGNWE
  SSEGWGAQPEGAGAQRNTNTPNNWDTAFGHPQAYQGPATGDDDDWDEDWDGPKSSSYFKD
  SESADAGGAQRGNSRASSSSMKIPLNKFPGFAKPGTEQYLLAKQLAKPKEKIPIIVGDYG
  PMWVYPTSTFDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVK
  FGSAIPIPSLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRHPVISESEVFQQFLNFRDEK
  EWKTGKRKAERDELAGVMIFSTMEPEAPDLDLVEIEQKCEAVGKFTKAMDDGVKELLTVG
  QEHWKRCTGPLPKEYQKIGKALQSLATVFSSSGYQGETDLNDAITEAGKTYEEIASLVAE
  QPKKDLHFLMECNHEYKGFLGCFPDIIGTHKGAIEKVKESDKLVATSKITLQDKQNMVKR
  VSIMSYALQAEMNHFHSNRIYDYNSVIRLYLEQQVQFYETIAEKLRQALSRFPVM
• Function: Involved in endocytosis and intracellular vesicle trafficking, both during interphase and at the end of mitosis. Required for efficient progress through mitosis and cytokinesis. Required for normal formation of the cleavage furrow at the end of mitosis. Plays a role in endocytosis via clathrin-coated pits, but also clathrin-independent, actin-dependent fluid-phase endocytosis. Plays a role in macropinocytosis. Promotes internalization of TNFR. Promotes degradation of EGFR after EGF signaling. Stimulates the GTPase activity of DNM1. Promotes DNM1 oligomerization. Promotes activation of the Arp2/3 complex by WASL, and thereby plays a role in the reorganization of the F-actin cytoskeleton. Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate and promotes membrane tubulation. Has lower affinity for membranes enriched in phosphatidylinositol 3-phosphate.
• Tissue Specificity: Widely expressed, with highest levels in heart and placenta, and lowest levels in thymus and peripheral blood leukocytes.
• KEGG Pathway: Salmonella infection (hsa05132)
• Reactome Pathway:
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[5]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[6]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Nephropathy	DISXWP4P	Strong	Altered Expression	[6]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[9]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[12]

5 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-9 (SNX9).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sorting nexin-9 (SNX9).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sorting nexin-9 (SNX9).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sorting nexin-9 (SNX9).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Sorting nexin-9 (SNX9).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sorting nexin-9 (SNX9).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sorting nexin-9 (SNX9).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sorting nexin-9 (SNX9).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorting nexin-9 (SNX9).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sorting nexin-9 (SNX9).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Sorting nexin-9 (SNX9).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sorting nexin-9 (SNX9).	[20]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Sorting nexin-9 (SNX9).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sorting nexin-9 (SNX9).	[22]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Sorting nexin-9 (SNX9).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sorting nexin-9 (SNX9).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sorting nexin-9 (SNX9).	[16]

References

• [1] WISP-2 in human gastric cancer and its potential metastatic suppressor role in gastric cancer cells mediated by JNK and PLC- pathways.Br J Cancer. 2015 Sep 15;113(6):921-33. doi: 10.1038/bjc.2015.285. Epub 2015 Aug 20.
• [2] The emerging role of WISP proteins in tumorigenesis and cancer therapy.J Transl Med. 2019 Jan 16;17(1):28. doi: 10.1186/s12967-019-1769-7.
• [3] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [4] Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer.Ann Surg Oncol. 2007 Jun;14(6):1909-18. doi: 10.1245/s10434-007-9376-x. Epub 2007 Apr 4.
• [5] WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14717-22. doi: 10.1073/pnas.95.25.14717.
• [6] Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.Sci Rep. 2017 Mar 7;7:43921. doi: 10.1038/srep43921.
• [7] Wingless-type inducible signaling pathway protein-1 (WISP1) adipokine and glucose homeostasis.J Cell Physiol. 2019 Aug;234(10):16966-16970. doi: 10.1002/jcp.28412. Epub 2019 Feb 26.
• [8] WISP2 exhibits its potential antitumor activity via targeting ERK and E-cadherin pathways in esophageal cancer cells.J Exp Clin Cancer Res. 2019 Feb 26;38(1):102. doi: 10.1186/s13046-019-1108-0.
• [9] Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature.J Cell Biol. 2017 Nov 6;216(11):3745-3765. doi: 10.1083/jcb.201704061. Epub 2017 Sep 18.
• [10] Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF- signaling.J Clin Invest. 2017 Jun 30;127(7):2541-2554. doi: 10.1172/JCI88696. Epub 2017 May 22.
• [11] SNX9 determines the surface levels of integrin 1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9.J Cell Physiol. 2019 Aug;234(10):17280-17294. doi: 10.1002/jcp.28346. Epub 2019 Feb 19.
• [12] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] 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.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] 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.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [24] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [25] 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.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.