Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVRL7J9)

• DOT Name: Next to BRCA1 gene 1 protein (NBR1)
• Synonyms: Cell migration-inducing gene 19 protein; Membrane component chromosome 17 surface marker 2; Neighbor of BRCA1 gene 1 protein; Protein 1A1-3B
• Gene Name: NBR1
• Related Disease:
  Dentatorubral-pallidoluysian atrophy
  Pancreatic ductal carcinoma
  Acute myelogenous leukaemia
  Advanced cancer
  Asthma
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Pneumonia
  Pneumonitis
  Coxsackie virus infection
  Enterovirus infection
• UniProt ID: NBR1_HUMAN
• PDB ID: 1WJ6; 2BKF; 2CP8; 2G4S; 2L8J; 2MGW; 2MJ5; 4OLE
• Pfam ID: PF16158 ; PF00564 ; PF00569
• Sequence:
  MEPQVTLNVTFKNEIQSFLVSDPENTTWADIEAMVKVSFDLNTIQIKYLDEENEEVSINS
  QGEYEEALKMAVKQGNQLQMQVHEGHHVVDEAPPPVVGAKRLAARAGKKPLAHYSSLVRV
  LGSDMKTPEDPAVQSFPLVPCDTDQPQDKPPDWFTSYLETFREQVVNETVEKLEQKLHEK
  LVLQNPSLGSCPSEVSMPTSEETLFLPENQFSWHIACNNCQRRIVGVRYQCSLCPSYNIC
  EDCEAGPYGHDTNHVLLKLRRPVVGSSEPFCHSKYSTPRLPAALEQVRLQKQVDKNFLKA
  EKQRLRAEKKQRKAEVKELKKQLKLHRKIHLWNSIHGLQSPKSPLGRPESLLQSNTLMLP
  LQPCTSVMPMLSAAFVDENLPDGTHLQPGTKFIKHWRMKNTGNVKWSADTKLKFMWGNLT
  LASTEKKDVLVPCLKAGHVGVVSVEFIAPALEGTYTSHWRLSHKGQQFGPRVWCSIIVDP
  FPSEESPDNIEKGMISSSKTDDLTCQQEETFLLAKEERQLGEVTEQTEGTAACIPQKAKN
  VASERELYIPSVDLLTAQDLLSFELLDINIVQELERVPHNTPVDVTPCMSPLPHDSPLIE
  KPGLGQIEEENEGAGFKALPDSMVSVKRKAENIASVEEAEEDLSGTQFVCETVIRSLTLD
  AAPDHNPPCRQKSLQMTFALPEGPLGNEKEEIIHIAEEEAVMEEEEDEEDEEEEDELKDE
  VQSQSSASSEDYIIILPECFDTSRPLGDSMYSSALSQPGLERGAEGKPGVEAGQEPAEAG
  ERLPGGENQPQEHSISDILTTSQTLETVPLIPEVVELPPSLPRSSPCVHHHGSPGVDLPV
  TIPEVSSVPDQIRGEPRGSSGLVNSRQKSYDHSRHHHGSSIAGGLVKGALSVAASAYKAL
  FAGPPVTAQPIISEDQTAALMAHLFEMGFCDRQLNLRLLKKHNYNILQVVTELLQLNNND
  WYSQRY
• Function: Ubiquitin-binding autophagy adapter that participates in different processes including host defense or intracellular homeostasis. Possesses a double function during the selective autophagy by acting as a shuttle bringing ubiquitinated proteins to autophagosomes and also by participating in the formation of protein aggregates. Plays a role in the regulation of the innate immune response by modulating type I interferon production and targeting ubiquitinated IRF3 for autophagic degradation. In response to oxidative stress, promotes an increase in SQSTM1 levels, phosphorylation, and body formation by preventing its autophagic degradation. In turn, activates the KEAP1-NRF2/NFE2L2 antioxidant pathway. Plays also non-autophagy role by mediating the shuttle of IL-12 to late endosome for subsequent secretion.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
• Reactome Pathway: Pexophagy (R-HSA-9664873)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Definitive	Genetic Variation	[1]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Asthma	DISW9QNS	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Pneumonia	DIS8EF3M	Strong	Biomarker	[4]
Pneumonitis	DIS88E0K	Strong	Biomarker	[4]
Coxsackie virus infection	DISY1VPA	Limited	Biomarker	[8]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[8]

17 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 Next to BRCA1 gene 1 protein (NBR1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Next to BRCA1 gene 1 protein (NBR1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Next to BRCA1 gene 1 protein (NBR1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Next to BRCA1 gene 1 protein (NBR1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Next to BRCA1 gene 1 protein (NBR1).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[19]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Next to BRCA1 gene 1 protein (NBR1).	[20]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Next to BRCA1 gene 1 protein (NBR1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[22]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[23]
Apilimod dimesylate	DM4N2O0	Phase 2	Apilimod dimesylate increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[27]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Next to BRCA1 gene 1 protein (NBR1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the ubiquitination of Next to BRCA1 gene 1 protein (NBR1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Next to BRCA1 gene 1 protein (NBR1).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Next to BRCA1 gene 1 protein (NBR1).	[26]

References

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• [6] Characterisation of a 161 kb deletion extending from the NBR1 to the BRCA1 genes in a French breast-ovarian cancer family.Hum Mutat. 2003 Jun;21(6):654. doi: 10.1002/humu.9148.
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• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [18] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [19] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [20] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [21] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
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• [24] PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell Mol Life Sci. 2016 Dec;73(24):4717-4737. doi: 10.1007/s00018-016-2309-8. Epub 2016 Jul 20.
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