Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTMT8UD)

• DOT Name: Nischarin (NISCH)
• Synonyms: Imidazoline receptor 1; I-1; IR1; Imidazoline receptor antisera-selected protein; hIRAS; Imidazoline-1 receptor; I1R; Imidazoline-1 receptor candidate protein; I-1 receptor candidate protein; I1R candidate protein
• Gene Name: NISCH
• UniProt ID: NISCH_HUMAN
• PDB ID: 3P0C; 8ESF
• Pfam ID: PF00787
• Sequence:
  MATARTFGPEREAEPAKEARVVGSELVDTYTVYIIQVTDGSHEWTVKHRYSDFHDLHEKL
  VAERKIDKNLLPPKKIIGKNSRSLVEKREKDLEVYLQKLLAAFPGVTPRVLAHFLHFHFY
  EINGITAALAEELFEKGEQLLGAGEVFAIGPLQLYAVTEQLQQGKPTCASGDAKTDLGHI
  LDFTCRLKYLKVSGTEGPFGTSNIQEQLLPFDLSIFKSLHQVEISHCDAKHIRGLVASKP
  TLATLSVRFSATSMKEVLVPEASEFDEWEPEGTTLEGPVTAVIPTWQALTTLDLSHNSVS
  EIDESVKLIPKIEFLDLSHNGLLVVDNLQHLYNLVHLDLSYNKLSSLEGLHTKLGNIKTL
  NLAGNLLESLSGLHKLYSLVNLDLRDNRIEQMEEVRSIGSLPCLEHVSLLNNPLSIIPDY
  RTKVLAQFGERASEVCLDDTVTTEKELDTVEVLKAIQKAKEVKSKLSNPEKKGGEDSRLS
  AAPCIRPSSSPPTVAPASASLPQPILSNQGIMFVQEEALASSLSSTDSLTPEHQPIAQGC
  SDSLESIPAGQAASDDLRDVPGAVGGASPEHAEPEVQVVPGSGQIIFLPFTCIGYTATNQ
  DFIQRLSTLIRQAIERQLPAWIEAANQREEGQGEQGEEEDEEEEEEEDVAENRYFEMGPP
  DVEEEEGGGQGEEEEEEEEDEEAEEERLALEWALGADEDFLLEHIRILKVLWCFLIHVQG
  SIRQFAACLVLTDFGIAVFEIPHQESRGSSQHILSSLRFVFCFPHGDLTEFGFLMPELCL
  VLKVRHSENTLFIISDAANLHEFHADLRSCFAPQHMAMLCSPILYGSHTSLQEFLRQLLT
  FYKVAGGCQERSQGCFPVYLVYSDKRMVQTAAGDYSGNIEWASCTLCSAVRRSCCAPSEA
  VKSAAIPYWLLLTPQHLNVIKADFNPMPNRGTHNCRNRNSFKLSRVPLSTVLLDPTRSCT
  QPRGAFADGHVLELLVGYRFVTAIFVLPHEKFHFLRVYNQLRASLQDLKTVVIAKTPGTG
  GSPQGSFADGQPAERRASNDQRPQEVPAEALAPAPAEVPAPAPAAASASGPAKTPAPAEA
  STSALVPEETPVEAPAPPPAEAPAQYPSEHLIQATSEENQIPSHLPACPSLRHVASLRGS
  AIIELFHSSIAEVENEELRHLMWSSVVFYQTPGLEVTACVLLSTKAVYFVLHDGLRRYFS
  EPLQDFWHQKNTDYNNSPFHISQCFVLKLSDLQSVNVGLFDQHFRLTGSTPMQVVTCLTR
  DSYLTHCFLQHLMVVLSSLERTPSPEPVDKDFYSEFGNKTTGKMENYELIHSSRVKFTYP
  SEEEIGDLTFTVAQKMAEPEKAPALSILLYVQAFQVGMPPPGCCRGPLRPKTLLLTSSEI
  FLLDEDCVHYPLPEFAKEPPQRDRYRLDDGRRVRDLDRVLMGYQTYPQALTLVFDDVQGH
  DLMGSVTLDHFGEVPGGPARASQGREVQWQVFVPSAESREKLISLLARQWEALCGRELPV
  ELTG
• Function: Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension. Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons. Acts as a modulator of Rac-regulated signal transduction pathways. Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity. Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation. Inhibits also LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation. Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells. Inhibits lamellipodia formation, when overexpressed. Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures.
• Tissue Specificity: Isoform 1, isoform 3 and isoform 4 are expressed in brain. Isoform 1 is expressed in endocrine tissues.
• Reactome Pathway:
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

9 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 Nischarin (NISCH).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nischarin (NISCH).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Nischarin (NISCH).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nischarin (NISCH).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nischarin (NISCH).	[5]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Nischarin (NISCH).	[6]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Nischarin (NISCH).	[6]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Nischarin (NISCH).	[7]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Nischarin (NISCH).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Nischarin (NISCH).	[8]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [7] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [8] 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.
• [9] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.