Details of Drug Off-Target (DOT)

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

• DOT Name: Neuromedin-B receptor (NMBR)
• Synonyms: NMB-R; Epididymis tissue protein Li 185a; Neuromedin-B-preferring bombesin receptor
• Gene Name: NMBR
• Related Disease:
  Ovarian cancer
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastrin-producing neuroendocrine tumor
  Hemochromatosis
  Hereditary hemochromatosis
  Lung cancer
  Lung carcinoma
  Progressive myoclonus epilepsy
  Schizophrenia
  Neoplasm
  Obesity
  Non-small-cell lung cancer
  Small-cell lung cancer
• UniProt ID: NMBR_HUMAN
• PDB ID: 8H0P
• Pfam ID: PF00001
• Sequence:
  MPSKSLSNLSVTTGANESGSVPEGWERDFLPASDGTTTELVIRCVIPSLYLLIITVGLLG
  NIMLVKIFITNSAMRSVPNIFISNLAAGDLLLLLTCVPVDASRYFFDEWMFGKVGCKLIP
  VIQLTSVGVSVFTLTALSADRYRAIVNPMDMQTSGALLRTCVKAMGIWVVSVLLAVPEAV
  FSEVARISSLDNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAKTLI
  KSAHNLPGEYNEHTKKQMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSL
  GHMIVTLVARVLSFGNSCVNPFALYLLSESFRRHFNSQLCCGRKSYQERGTSYLLSSSAV
  RMTSLKSNAKNMVTNSVLLNGHSMKQEMAL
• Function: Receptor for neuromedin-B. Contributes to the maintenance of basal sigh rate through signaling in the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity. Contributes to the induction of sneezing following exposure to chemical irritants or allergens which causes release of NMB by nasal sensory neurons and activation of NMBR-expressing neurons in the sneeze-evoking region of the brainstem. These in turn activate neurons of the caudal ventral respiratory group, giving rise to the sneezing response. Contributes to induction of acute itch, possibly through its activation on dorsal root ganglion neurons by the NMB peptide. Plays a role in the innate immune response to influenza A virus infection by enhancing interferon alpha expression and reducing expression of IL6. Plays a role in CSF1-induced proliferation of osteoclast precursors by contributing to the positive regulation of the expression of the CSF1 receptor CSF1R.
• Tissue Specificity: Expressed in epididymis (at protein level).
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Gastrin-producing neuroendocrine tumor	DIS8TYKO	Strong	Biomarker	[4]
Hemochromatosis	DISAPY0H	Strong	Genetic Variation	[5]
Hereditary hemochromatosis	DISVG5MT	Strong	Genetic Variation	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Obesity	DIS47Y1K	moderate	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[9]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuromedin-B receptor (NMBR).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Neuromedin-B receptor (NMBR).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuromedin-B receptor (NMBR).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Neuromedin-B receptor (NMBR).	[13]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate increases the methylation of Neuromedin-B receptor (NMBR).	[14]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Neuromedin-B receptor (NMBR).	[15]

References

• [1] The presence of receptors for bombesin/GRP and mRNA for three receptor subtypes in human ovarian epithelial cancers.Regul Pept. 2000 Jun 30;90(1-3):77-84. doi: 10.1016/s0167-0115(00)00114-2.
• [2] A possible new target in lung-cancer cells: The orphan receptor, bombesin receptor subtype-3.Peptides. 2018 Mar;101:213-226. doi: 10.1016/j.peptides.2018.01.016. Epub 2018 Feb 2.
• [3] Hypoxia regulates the expression of the neuromedin B receptor through a mechanism dependent on hypoxia-inducible factor-1.PLoS One. 2013 Dec 9;8(12):e82868. doi: 10.1371/journal.pone.0082868. eCollection 2013.
• [4] Mechanisms of bombesin on growth of gastrinoma (PT) in vivo.Dig Dis Sci. 1996 Nov;41(11):2180-6. doi: 10.1007/BF02071398.
• [5] Impact of natural neuromedin-B receptor variants on iron metabolism.Am J Hematol. 2020 Feb;95(2):167-177. doi: 10.1002/ajh.25679. Epub 2019 Dec 16.
• [6] Two distinct bombesin receptor subtypes are expressed and functional in human lung carcinoma cells.J Biol Chem. 1991 Oct 5;266(28):18771-9.
• [7] PDE7B, NMBR and EPM2A Variants and Schizophrenia: A Case-Control and Pharmacogenetics Study.Neuropsychobiology. 2016;73(3):160-8. doi: 10.1159/000445295. Epub 2016 Apr 20.
• [8] Neuromedin B receptor disruption impairs adipogenesis in mice and 3T3-L1 cells.J Mol Endocrinol. 2019 Jul;63(1):93-102. doi: 10.1530/JME-19-0032.
• [9] Detection of tumor specific gene expression in bone marrow and peripheral blood from patients with small cell lung carcinoma.Cancer. 2003 Feb 15;97(4):1057-62. doi: 10.1002/cncr.11108.
• [10] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [11] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [12] 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.
• [13] 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.
• [14] DNA methylation modifies urine biomarker levels in 1,6-hexamethylene diisocyanate exposed workers: a pilot study. Toxicol Lett. 2014 Dec 1;231(2):217-26. doi: 10.1016/j.toxlet.2014.10.024. Epub 2014 Oct 22.
• [15] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.