Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUQH74P)

• DOT Name: Netrin-1 (NTN1)
• Synonyms: Epididymis tissue protein Li 131P
• Gene Name: NTN1
• Related Disease:
  Mirror movements 4
  Familial congenital mirror movements
• UniProt ID: NET1_HUMAN
• PDB ID: 4URT; 6FKQ; 7NDG; 7NE0; 7NE1
• Pfam ID: PF00053 ; PF00055 ; PF01759
• Sequence:
  MMRAVWEALAALAAVACLVGAVRGGPGLSMFAGQAAQPDPCSDENGHPRRCIPDFVNAAF
  GKDVRVSSTCGRPPARYCVVSERGEERLRSCHLCNASDPKKAHPPAFLTDLNNPHNLTCW
  QSENYLQFPHNVTLTLSLGKKFEVTYVSLQFCSPRPESMAIYKSMDYGRTWVPFQFYSTQ
  CRKMYNRPHRAPITKQNEQEAVCTDSHTDMRPLSGGLIAFSTLDGRPSAHDFDNSPVLQD
  WVTATDIRVAFSRLHTFGDENEDDSELARDSYFYAVSDLQVGGRCKCNGHAARCVRDRDD
  SLVCDCRHNTAGPECDRCKPFHYDRPWQRATAREANECVACNCNLHARRCRFNMELYKLS
  GRKSGGVCLNCRHNTAGRHCHYCKEGYYRDMGKPITHRKACKACDCHPVGAAGKTCNQTT
  GQCPCKDGVTGITCNRCAKGYQQSRSPIAPCIKIPVAPPTTAASSVEEPEDCDSYCKASK
  GKLKINMKKYCKKDYAVQIHILKADKAGDWWKFTVNIISVYKQGTSRIRRGDQSLWIRSR
  DIACKCPKIKPLKKYLLLGNAEDSPDQSGIVADKSSLVIQWRDTWARRLRKFQQREKKGK
  CKKA
• Function: Netrins control guidance of CNS commissural axons and peripheral motor axons. Its association with either DCC or some UNC5 receptors will lead to axon attraction or repulsion, respectively. Binding to UNC5C might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion. Involved in dorsal root ganglion axon projection towards the spinal cord. It also serves as a survival factor via its association with its receptors which prevent the initiation of apoptosis. Involved in tumorigenesis by regulating apoptosis.
• Tissue Specificity: Widely expressed in normal adult tissues with highest levels in heart, small intestine, colon, liver and prostate. Reduced expression in brain tumors and neuroblastomas. Expressed in epididymis (at protein level).
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  DSCAM interactions (R-HSA-376172)
  DCC mediated attractive signaling (R-HSA-418885)
  Netrin mediated repulsion signals (R-HSA-418886)
  Role of second messengers in netrin-1 signaling (R-HSA-418890)
  Regulation of commissural axon pathfinding by SLIT and ROBO (R-HSA-428542)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mirror movements 4	DIS1492E	Strong	Autosomal dominant	[1]
Familial congenital mirror movements	DISJLV92	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Netrin-1 (NTN1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Netrin-1 (NTN1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Netrin-1 (NTN1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Netrin-1 (NTN1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Netrin-1 (NTN1).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Netrin-1 (NTN1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Netrin-1 (NTN1).	[7]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Netrin-1 (NTN1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Netrin-1 (NTN1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Netrin-1 (NTN1).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Netrin-1 (NTN1).	[12]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Netrin-1 (NTN1).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
BADGE	DMCK5DG	Investigative	BADGE decreases the response to substance of Netrin-1 (NTN1).	[14]

References

• [1] Mutations in the netrin-1 gene cause congenital mirror movements. J Clin Invest. 2017 Nov 1;127(11):3923-3936. doi: 10.1172/JCI95442. Epub 2017 Sep 25.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [13] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [14] Recombinant Netrin-1 binding UNC5B receptor attenuates neuroinflammation and brain injury via PPAR/NFB signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun. 2018 Mar;69:190-202. doi: 10.1016/j.bbi.2017.11.012. Epub 2017 Nov 21.