Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVZD4H6)

• DOT Name: BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2)
• Gene Name: BNIP2
• Related Disease:
  Neuroblastoma
  Colorectal adenocarcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: BNIP2_HUMAN
• Pfam ID: PF12496 ; PF13716
• Sequence:
  MEGVELKEEWQDEDFPIPLPEDDSIEADILAITGPEDQPGSLEVNGNKVRKKLMAPDISL
  TLDPSDGSVLSDDLDESGEIDLDGLDTPSENSNEFEWEDDLPKPKTTEVIRKGSITEYTA
  AEEKEDGRRWRMFRIGEQDHRVDMKAIEPYKKVISHGGYYGDGLNAIVVFAVCFMPESSQ
  PNYRYLMDNLFKYVIGTLELLVAENYMIVYLNGATTRRKMPSLGWLRKCYQQIDRRLRKN
  LKSLIIVHPSWFIRTLLAVTRPFISSKFSQKIRYVFNLAELAELVPMEYVGIPECIKQVD
  QELNGKQDEPKNEQ
• Function: Implicated in the suppression of cell death. Interacts with the BCL-2 and adenovirus E1B 19 kDa proteins.
• Reactome Pathway: Myogenesis (R-HSA-525793)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	moderate	Genetic Variation	[1]
Colorectal adenocarcinoma	DISPQOUB	Limited	Biomarker	[2]
Prostate cancer	DISF190Y	Limited	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[7]
Menthol	DMG2KW7	Approved	Menthol increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[9]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[10]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[11]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2).	[18]

References

• [1] Increased expression of proapoptotic BMCC1, a novel gene with the BNIP2 and Cdc42GAP homology (BCH) domain, is associated with favorable prognosis in human neuroblastomas.Oncogene. 2006 Mar 23;25(13):1931-42. doi: 10.1038/sj.onc.1209225.
• [2] miR-20a targets BNIP2 and contributes chemotherapeutic resistance in colorectal adenocarcinoma SW480 and SW620 cell lines.Acta Biochim Biophys Sin (Shanghai). 2011 Mar;43(3):217-25. doi: 10.1093/abbs/gmq125. Epub 2011 Jan 17.
• [3] BMCC1 is an AP-2 associated endosomal protein in prostate cancer cells.PLoS One. 2013 Sep 6;8(9):e73880. doi: 10.1371/journal.pone.0073880. eCollection 2013.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Identification of estrogen-responsive genes in neuroblastoma SK-ER3 cells. J Neurosci. 1997 Jun 15;17(12):4591-9. doi: 10.1523/JNEUROSCI.17-12-04591.1997.
• [8] 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.
• [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] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [11] Triggering of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin induces Fas/CD95-mediated apoptosis of urothelial cancer cells in an ATM-dependent manner. Carcinogenesis. 2009 Aug;30(8):1320-9. doi: 10.1093/carcin/bgp138. Epub 2009 Jun 5.
• [12] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [13] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.