Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI6LD27)

• DOT Name: BAG family molecular chaperone regulator 2 (BAG2)
• Synonyms: BAG-2; Bcl-2-associated athanogene 2
• Gene Name: BAG2
• Related Disease:
  Alzheimer disease
  B-cell neoplasm
  Neoplasm
  Oral cancer
  Triple negative breast cancer
  Neuroblastoma
• UniProt ID: BAG2_HUMAN
• Sequence:
  MAQAKINAKANEGRFCRSSSMADRSSRLLESLDQLELRVEALREAATAVEQEKEILLEMI
  HSIQNSQDMRQISDGEREELNLTANRLMGRTLTVEVSVETIRNPQQQESLKHATRIIDEV
  VNKFLDDLGNAKSHLMSLYSACSSEVPHGPVDQKFQSIVIGCALEDQKKIKRRLETLLRN
  IENSDKAIKLLEHSKGAGSKTLQQNAESRFN
• Function: Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Oral cancer	DISLD42D	Strong	Altered Expression	[4]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[5]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	BAG family molecular chaperone regulator 2 (BAG2) affects the response to substance of Etoposide.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of BAG family molecular chaperone regulator 2 (BAG2).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of BAG family molecular chaperone regulator 2 (BAG2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of BAG family molecular chaperone regulator 2 (BAG2).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[14]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[17]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[20]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[17]
Calphostin C	DM9X2D0	Terminated	Calphostin C decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[25]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[26]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of BAG family molecular chaperone regulator 2 (BAG2).	[27]

References

• [1] Anandamide Effects in a Streptozotocin-Induced Alzheimer's Disease-Like Sporadic Dementia in Rats.Front Neurosci. 2018 Sep 21;12:653. doi: 10.3389/fnins.2018.00653. eCollection 2018.
• [2] MicroRNA-1180 is associated with growth and apoptosis in prostate cancer via TNF receptor associated factor 1 expression regulation and nuclear factor-B signaling pathway activation.Oncol Lett. 2018 Apr;15(4):4775-4780. doi: 10.3892/ol.2018.7914. Epub 2018 Jan 31.
• [3] BAG2 promotes tumorigenesis through enhancing mutant p53 protein levels and function.Elife. 2015 Aug 13;4:e08401. doi: 10.7554/eLife.08401.
• [4] Over-expression of Bcl2-associated athanogene 2 in oral cancer promotes cellular proliferation and is associated with poor prognosis.Arch Oral Biol. 2019 Jun;102:164-170. doi: 10.1016/j.archoralbio.2019.04.015. Epub 2019 Apr 29.
• [5] Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells.Cell Rep. 2017 Dec 5;21(10):2952-2964. doi: 10.1016/j.celrep.2017.11.026.
• [6] BAG2 Is Repressed by NF-B Signaling, and Its Overexpression Is Sufficient to Shift A1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma.J Mol Neurosci. 2015 Sep;57(1):83-9. doi: 10.1007/s12031-015-0579-5. Epub 2015 May 19.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] 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.
• [16] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [17] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [18] 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.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
• [23] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [27] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [28] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.