Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNK9ALK)

• DOT Name: Plexin-D1 (PLXND1)
• Gene Name: PLXND1
• Related Disease:
  Congenital heart defects, multiple types, 9
  Endometriosis
  Gastric cancer
  Melanocytic nevus
  Metabolic disorder
  Neoplasm
  Neuralgia
  Stomach cancer
  Advanced cancer
  Brain neoplasm
  Melanoma
  Mobius syndrome
  Persistent truncus arteriosus
  Metastatic malignant neoplasm
• UniProt ID: PLXD1_HUMAN
• PDB ID: 3H6N
• Pfam ID: PF08337 ; PF20170 ; PF01437 ; PF01403 ; PF01833 ; PF17960
• Sequence:
  MAPRAAGGAPLSARAAAASPPPFQTPPRCPVPLLLLLLLGAARAGALEIQRRFPSPTPTN
  NFALDGAAGTVYLAAVNRLYQLSGANLSLEAEAAVGPVPDSPLCHAPQLPQASCEHPRRL
  TDNYNKILQLDPGQGLVVVCGSIYQGFCQLRRRGNISAVAVRFPPAAPPAEPVTVFPSML
  NVAANHPNASTVGLVLPPAAGAGGSRLLVGATYTGYGSSFFPRNRSLEDHRFENTPEIAI
  RSLDTRGDLAKLFTFDLNPSDDNILKIKQGAKEQHKLGFVSAFLHPSDPPPGAQSYAYLA
  LNSEARAGDKESQARSLLARICLPHGAGGDAKKLTESYIQLGLQCAGGAGRGDLYSRLVS
  VFPARERLFAVFERPQGSPAARAAPAALCAFRFADVRAAIRAARTACFVEPAPDVVAVLD
  SVVQGTGPACERKLNIQLQPEQLDCGAAHLQHPLSILQPLKATPVFRAPGLTSVAVASVN
  NYTAVFLGTVNGRLLKINLNESMQVVSRRVVTVAYGEPVHHVMQFDPADSGYLYLMTSHQ
  MARVKVAACNVHSTCGDCVGAADAYCGWCALETRCTLQQDCTNSSQQHFWTSASEGPSRC
  PAMTVLPSEIDVRQEYPGMILQISGSLPSLSGMEMACDYGNNIRTVARVPGPAFGHQIAY
  CNLLPRDQFPPFPPNQDHVTVEMSVRVNGRNIVKANFTIYDCSRTAQVYPHTACTSCLSA
  QWPCFWCSQQHSCVSNQSRCEASPNPTSPQDCPRTLLSPLAPVPTGGSQNILVPLANTAF
  FQGAALECSFGLEEIFEAVWVNESVVRCDQVVLHTTRKSQVFPLSLQLKGRPARFLDSPE
  PMTVMVYNCAMGSPDCSQCLGREDLGHLCMWSDGCRLRGPLQPMAGTCPAPEIHAIEPLS
  GPLDGGTLLTIRGRNLGRRLSDVAHGVWIGGVACEPLPDRYTVSEEIVCVTGPAPGPLSG
  VVTVNASKEGKSRDRFSYVLPLVHSLEPTMGPKAGGTRITIHGNDLHVGSELQVLVNDTD
  PCTELMRTDTSIACTMPEGALPAPVPVCVRFERRGCVHGNLTFWYMQNPVITAISPRRSP
  VSGGRTITVAGERFHMVQNVSMAVHHIGREPTLCKVLNSTLITCPSPGALSNASAPVDFF
  INGRAYADEVAVAEELLDPEEAQRGSRFRLDYLPNPQFSTAKREKWIKHHPGEPLTLVIH
  KEQDSLGLQSHEYRVKIGQVSCDIQIVSDRIIHCSVNESLGAAVGQLPITIQVGNFNQTI
  ATLQLGGSETAIIVSIVICSVLLLLSVVALFVFCTKSRRAERYWQKTLLQMEEMESQIRE
  EIRKGFAELQTDMTDLTKELNRSQGIPFLEYKHFVTRTFFPKCSSLYEERYVLPSQTLNS
  QGSSQAQETHPLLGEWKIPESCRPNMEEGISLFSSLLNNKHFLIVFVHALEQQKDFAVRD
  RCSLASLLTIALHGKLEYYTSIMKELLVDLIDASAAKNPKLMLRRTESVVEKMLTNWMSI
  CMYSCLRETVGEPFFLLLCAIKQQINKGSIDAITGKARYTLSEEWLLRENIEAKPRNLNV
  SFQGCGMDSLSVRAMDTDTLTQVKEKILEAFCKNVPYSQWPRAEDVDLEWFASSTQSYIL
  RDLDDTSVVEDGRKKLNTLAHYKIPEGASLAMSLIDKKDNTLGRVKDLDTEKYFHLVLPT
  DELAEPKKSHRQSHRKKVLPEIYLTRLLSTKGTLQKFLDDLFKAILSIREDKPPLAVKYF
  FDFLEEQAEKRGISDPDTLHIWKTNSLPLRFWVNILKNPQFVFDIDKTDHIDACLSVIAQ
  AFIDACSISDLQLGKDSPTNKLLYAKEIPEYRKIVQRYYKQIQDMTPLSEQEMNAHLAEE
  SRKYQNEFNTNVAMAEIYKYAKRYRPQIMAALEANPTARRTQLQHKFEQVVALMEDNIYE
  CYSEA
• Function: Cell surface receptor for SEMA4A and for class 3 semaphorins, such as SEMA3A, SEMA3C and SEMA3E. Plays an important role in cell-cell signaling, and in regulating the migration of a wide spectrum of cell types. Regulates the migration of thymocytes in the medulla. Regulates endothelial cell migration. Plays an important role in ensuring the specificity of synapse formation. Required for normal development of the heart and vasculature. Mediates anti-angiogenic signaling in response to SEMA3E.
• Tissue Specificity: Detected at low levels in heart, placenta, lung, skeletal muscle, kidney, thymus and liver. Detected at very low levels in brain, colon, spleen, small intestine and peripheral blood leukocytes.
• Reactome Pathway:
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  RND2 GTPase cycle (R-HSA-9696270)
  Other semaphorin interactions (R-HSA-416700)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital heart defects, multiple types, 9	DIS8RX4B	Strong	Autosomal recessive	[1]
Endometriosis	DISX1AG8	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Melanocytic nevus	DISYS32D	Strong	Altered Expression	[4]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neuralgia	DISWO58J	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Brain neoplasm	DISY3EKS	moderate	Altered Expression	[8]
Melanoma	DIS1RRCY	moderate	Altered Expression	[8]
Mobius syndrome	DIS9YXP5	Supportive	Autosomal dominant	[9]
Persistent truncus arteriosus	DISRZ8EA	Supportive	Autosomal recessive	[1]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[6]

4 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 Plexin-D1 (PLXND1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Plexin-D1 (PLXND1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Plexin-D1 (PLXND1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Plexin-D1 (PLXND1).	[19]

8 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 Plexin-D1 (PLXND1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Plexin-D1 (PLXND1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Plexin-D1 (PLXND1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Plexin-D1 (PLXND1).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Plexin-D1 (PLXND1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Plexin-D1 (PLXND1).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Plexin-D1 (PLXND1).	[20]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Plexin-D1 (PLXND1).	[21]

References

• [1] Isolated truncus arteriosus associated with a mutation in the plexin-D1 gene. Am J Med Genet A. 2013 Dec;161A(12):3115-20. doi: 10.1002/ajmg.a.36194. Epub 2013 Oct 29.
• [2] The Expression and Cellular Localisation of Neurotrophin and Neural Guidance Molecules in Peritoneal Ectopic Lesions.Mol Neurobiol. 2019 Jun;56(6):4013-4022. doi: 10.1007/s12035-018-1348-6. Epub 2018 Sep 25.
• [3] Enhanced expression of semaphorin 3E is involved in the gastric cancer development.Int J Oncol. 2016 Sep;49(3):887-94. doi: 10.3892/ijo.2016.3593. Epub 2016 Jun 30.
• [4] Semaphorin 3E expression correlates inversely with Plexin D1 during tumor progression.Am J Pathol. 2008 Dec;173(6):1873-81. doi: 10.2353/ajpath.2008.080136. Epub 2008 Oct 30.
• [5] Elucidating the role of plexin D1 in body fat distribution and susceptibility to metabolic disease using a zebrafish model system.Adipocyte. 2017 Oct 2;6(4):277-283. doi: 10.1080/21623945.2017.1356504. Epub 2017 Aug 9.
• [6] Divergent roles of Plexin D1 in cancer.Biochim Biophys Acta Rev Cancer. 2019 Aug;1872(1):103-110. doi: 10.1016/j.bbcan.2019.05.004. Epub 2019 May 30.
• [7] A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain.Ann Neurol. 2018 Aug;84(2):208-224. doi: 10.1002/ana.25279. Epub 2018 Sep 3.
• [8] Plexin D1 is ubiquitously expressed on tumor vessels and tumor cells in solid malignancies.BMC Cancer. 2009 Aug 25;9:297. doi: 10.1186/1471-2407-9-297.
• [9] De novo mutations in PLXND1 and REV3L cause M?bius syndrome. Nat Commun. 2015 Jun 12;6:7199. doi: 10.1038/ncomms8199.
• [10] 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.
• [11] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] 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.
• [19] 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.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] 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.