Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVPS7S0)

• DOT Name: Sorting nexin-27 (SNX27)
• Gene Name: SNX27
• Related Disease:
  Cone-rod dystrophy 2
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Congenital hydrocephalus
  Hydrocephalus
  Intellectual disability
  Neoplasm
  Respiratory failure
  Intellectual disability, autosomal recessive 1
  Invasive breast carcinoma
• UniProt ID: SNX27_HUMAN
• PDB ID: 4HAS; 5ZN9; 6SAK; 7CT1; 7E0B; 7P72; 7PCB
• Pfam ID: PF00595 ; PF00787 ; PF00788
• Sequence:
  MADEDGEGIHPSAPHRNGGGGGGGGSGLHCAGNGGGGGGGPRVVRIVKSESGYGFNVRGQ
  VSEGGQLRSINGELYAPLQHVSAVLPGGAADRAGVRKGDRILEVNHVNVEGATHKQVVDL
  IRAGEKELILTVLSVPPHEADNLDPSDDSLGQSFYDYTEKQAVPISVPRYKHVEQNGEKF
  VVYNVYMAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGLE
  EYLEKVCSIRVIGESDIMQEFLSESDENYNGVSDVELRVALPDGTTVTVRVKKNSTTDQV
  YQAIAAKVGMDSTTVNYFALFEVISHSFVRKLAPNEFPHKLYIQNYTSAVPGTCLTIRKW
  LFTTEEEILLNDNDLAVTYFFHQAVDDVKKGYIKAEEKSYQLQKLYEQRKMVMYLNMLRT
  CEGYNEIIFPHCACDSRRKGHVITAISITHFKLHACTEEGQLENQVIAFEWDEMQRWDTD
  EEGMAFCFEYARGEKKPRWVKIFTPYFNYMHECFERVFCELKWRKENIFQMARSQQRDVA
  T
• Function: Involved in the retrograde transport from endosome to plasma membrane, a trafficking pathway that promotes the recycling of internalized transmembrane proteins. Following internalization, endocytosed transmembrane proteins are delivered to early endosomes and recycled to the plasma membrane instead of being degraded in lysosomes. SNX27 specifically binds and directs sorting of a subset of transmembrane proteins containing a PDZ-binding motif at the C-terminus: following interaction with target transmembrane proteins, associates with the retromer complex, preventing entry into the lysosomal pathway, and promotes retromer-tubule based plasma membrane recycling. SNX27 also binds with the WASH complex. Interacts with membranes containing phosphatidylinositol-3-phosphate (PtdIns(3P)). May participate in establishment of natural killer cell polarity. Recruits CYTIP to early endosomes.
• Tissue Specificity: Widely expressed. Expressed in cells of hematopoietic origin (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 2	DISX2RWY	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Congenital hydrocephalus	DIS7O6UL	Strong	Biomarker	[4]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[7]
Intellectual disability, autosomal recessive 1	DISINB3A	moderate	Biomarker	[8]
Invasive breast carcinoma	DISANYTW	Limited	Altered Expression	[3]

8 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 Sorting nexin-27 (SNX27).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sorting nexin-27 (SNX27).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sorting nexin-27 (SNX27).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sorting nexin-27 (SNX27).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sorting nexin-27 (SNX27).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorting nexin-27 (SNX27).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sorting nexin-27 (SNX27).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sorting nexin-27 (SNX27).	[16]

References

• [1] Snx27 Deletion Promotes Recovery From Spinal Cord Injury by Neuroprotection and Reduces Macrophage/Microglia Proliferation.Front Neurol. 2018 Dec 13;9:1059. doi: 10.3389/fneur.2018.01059. eCollection 2018.
• [2] Downregulation of SNX27 expression does not exacerbate amyloidogenesis in the APP/PS1 Alzheimer's disease mouse model.Neurobiol Aging. 2019 May;77:144-153. doi: 10.1016/j.neurobiolaging.2019.01.011. Epub 2019 Jan 25.
• [3] SNX27-retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis.J Cell Biol. 2020 Jan 6;219(1):e201812098. doi: 10.1083/jcb.201812098.
• [4] SNX27 Deletion Causes Hydrocephalus by Impairing Ependymal Cell Differentiation and Ciliogenesis.J Neurosci. 2016 Dec 14;36(50):12586-12597. doi: 10.1523/JNEUROSCI.1620-16.2016.
• [5] Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome.Nat Med. 2013 Apr;19(4):473-80. doi: 10.1038/nm.3117. Epub 2013 Mar 24.
• [6] Deletion of sorting nexin 27 suppresses proliferation in highly aggressive breast cancer MDA-MB-231 cells in vitro and in vivo.BMC Cancer. 2019 Jun 10;19(1):555. doi: 10.1186/s12885-019-5769-z.
• [7] Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities.Clin Genet. 2020 Mar;97(3):437-446. doi: 10.1111/cge.13675. Epub 2019 Dec 11.
• [8] Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans.Nucleic Acids Res. 2017 Sep 19;45(16):9467-9480. doi: 10.1093/nar/gkx660.
• [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] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [11] 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.
• [12] 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.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] 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.
• [15] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [16] 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.