Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZL256E)

• DOT Name: Neuropilin-2 (NRP2)
• Synonyms: Vascular endothelial cell growth factor 165 receptor 2
• Gene Name: NRP2
• UniProt ID: NRP2_HUMAN
• PDB ID: 2QQJ; 2QQK; 2QQL; 2QQO; 4QDQ; 4QDR; 4QDS; 5DN2; 5DQ0; 6GH8; 6TDB; 6TJT; 7M22; 7T4S; 8IVW; 8IVX
• Pfam ID: PF00431 ; PF11980 ; PF00754 ; PF00629
• Sequence:
  MDMFPLTWVFLALYFSRHQVRGQPDPPCGGRLNSKDAGYITSPGYPQDYPSHQNCEWIVY
  APEPNQKIVLNFNPHFEIEKHDCKYDFIEIRDGDSESADLLGKHCGNIAPPTIISSGSML
  YIKFTSDYARQGAGFSLRYEIFKTGSEDCSKNFTSPNGTIESPGFPEKYPHNLDCTFTIL
  AKPKMEIILQFLIFDLEHDPLQVGEGDCKYDWLDIWDGIPHVGPLIGKYCGTKTPSELRS
  STGILSLTFHTDMAVAKDGFSARYYLVHQEPLENFQCNVPLGMESGRIANEQISASSTYS
  DGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFLTMLTAIATQGAISRETQNGYYVKS
  YKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLNKLHAPLLTRFVRIRPQTWHSGIAL
  RLELFGCRVTDAPCSNMLGMLSGLIADSQISASSTQEYLWSPSAARLVSSRSGWFPRIPQ
  AQPGEEWLQVDLGTPKTVKGVIIQGARGGDSITAVEARAFVRKFKVSYSLNGKDWEYIQD
  PRTQQPKLFEGNMHYDTPDIRRFDPIPAQYVRVYPERWSPAGIGMRLEVLGCDWTDSKPT
  VETLGPTVKSEETTTPYPTEEEATECGENCSFEDDKDLQLPSGFNCNFDFLEEPCGWMYD
  HAKWLRTTWASSSSPNDRTFPDDRNFLRLQSDSQREGQYARLISPPVHLPRSPVCMEFQY
  QATGGRGVALQVVREASQESKLLWVIREDQGGEWKHGRIILPSYDMEYQIVFEGVIGKGR
  SGEIAIDDIRISTDVPLENCMEPISAFAGENFKVDIPEIHEREGYEDEIDDEYEVDWSNS
  SSATSGSGAPSTDKEKSWLYTLDPILITIIAMSSLGVLLGATCAGLLLYCTCSYSGLSSR
  SCTTLENYNFELYDGLKHKVKMNHQKCCSEA
• Function: High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF.; (Microbial infection) Acts as a receptor for human cytomegalovirus pentamer-dependent entry in epithelial and endothelial cells.
• Reactome Pathway:
  NrCAM interactions (R-HSA-447038)
  Neurophilin interactions with VEGF and VEGFR (R-HSA-194306)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Neuropilin-2 (NRP2).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuropilin-2 (NRP2).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neuropilin-2 (NRP2).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Neuropilin-2 (NRP2).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neuropilin-2 (NRP2).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Neuropilin-2 (NRP2).	[7]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Neuropilin-2 (NRP2).	[8]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Neuropilin-2 (NRP2).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuropilin-2 (NRP2).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Neuropilin-2 (NRP2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neuropilin-2 (NRP2).	[12]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Neuropilin-2 (NRP2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuropilin-2 (NRP2).	[1]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone affects the expression of Neuropilin-2 (NRP2).	[15]

3 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 Neuropilin-2 (NRP2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuropilin-2 (NRP2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Neuropilin-2 (NRP2).	[14]

References

• [1] 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.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [9] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [10] Genistein affects the expression of genes involved in blood pressure regulation and angiogenesis in primary human endothelial cells. Nutr Metab Cardiovasc Dis. 2006 Jan;16(1):35-43. doi: 10.1016/j.numecd.2005.03.003. Epub 2005 Jul 28.
• [11] 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.
• [12] 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.
• [13] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [14] 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.
• [15] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.