Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUPX3M2)

• DOT Name: BAG family molecular chaperone regulator 4 (BAG4)
• Synonyms: BAG-4; Bcl-2-associated athanogene 4; Silencer of death domains
• Gene Name: BAG4
• Related Disease:
  Acute lymphocytic leukaemia
  Adenoma
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Lung squamous cell carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Gastric cancer
  Melanoma
  Stomach cancer
  Multiple sclerosis
  Epithelial ovarian cancer
• UniProt ID: BAG4_HUMAN
• PDB ID: 1M62; 1M7K
• Pfam ID: PF02179
• Sequence:
  MSALRRSGYGPSDGPSYGRYYGPGGGDVPVHPPPPLYPLRPEPPQPPISWRVRGGGPAET
  TWLGEGGGGDGYYPSGGAWPEPGRAGGSHQEQPPYPSYNSNYWNSTARSRAPYPSTYPVR
  PELQGQSLNSYTNGAYGPTYPPGPGANTASYSGAYYAPGYTQTSYSTEVPSTYRSSGNSP
  TPVSRWIYPQQDCQTEAPPLRGQVPGYPPSQNPGMTLPHYPYGDGNRSVPQSGPTVRPQE
  DAWASPGAYGMGGRYPWPSSAPSAPPGNLYMTESTSPWPSSGSPQSPPSPPVQQPKDSSY
  PYSQSDQSMNRHNFPCSVHQYESSGTVNNDDSDLLDSQVQYSAEPQLYGNATSDHPNNQD
  QSSSLPEECVPSDESTPPSIKKIIHVLEKVQYLEQEVEEFVGKKTDKAYWLLEEMLTKEL
  LELDSVETGGQDSVRQARKEAVCKIQAILEKLEKKGL
• Function: Inhibits the chaperone activity of HSP70/HSC70 by promoting substrate release. Prevents constitutive TNFRSF1A signaling. Negative regulator of PRKN translocation to damaged mitochondria.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: TNF sig.ling pathway (hsa04668)
• Reactome Pathway:
  Signaling by FGFR1 in disease (R-HSA-5655302)
  TNF signaling (R-HSA-75893)
  Signaling by plasma membrane FGFR1 fusions (R-HSA-8853336)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[7]
Gastric cancer	DISXGOUK	moderate	Biomarker	[6]
Melanoma	DIS1RRCY	moderate	Altered Expression	[8]
Stomach cancer	DISKIJSX	moderate	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Disputed	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[10]

12 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 BAG family molecular chaperone regulator 4 (BAG4).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[13]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of BAG family molecular chaperone regulator 4 (BAG4).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[15]
Menthol	DMG2KW7	Approved	Menthol increases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[16]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[17]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[18]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[22]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[23]
Staurosporine	DM0E9BR	Investigative	Staurosporine decreases the expression of BAG family molecular chaperone regulator 4 (BAG4).	[24]

2 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 affects the methylation of BAG family molecular chaperone regulator 4 (BAG4).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of BAG family molecular chaperone regulator 4 (BAG4).	[21]

References

• [1] Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute lymphoblastic leukemia.PLoS One. 2014 Jul 25;9(7):e103383. doi: 10.1371/journal.pone.0103383. eCollection 2014.
• [2] Protein and glycomic plasma markers for early detection of adenoma and colon cancer.Gut. 2018 Mar;67(3):473-484. doi: 10.1136/gutjnl-2016-312794. Epub 2016 Nov 7.
• [3] Significance of SODD expression in childhood acute lymphoblastic leukemia and its influence on chemotherapy.Genet Mol Res. 2014 Mar 24;13(1):2020-31. doi: 10.4238/2014.March.24.6.
• [4] SODD promotes glucose uptake of colorectal cancer cells via AKT pathway.Cell Biol Int. 2017 Oct 31. doi: 10.1002/cbin.10907. Online ahead of print.
• [5] FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer.Clin Cancer Res. 2014 Aug 1;20(15):4107-14. doi: 10.1158/1078-0432.CCR-14-0284. Epub 2014 May 21.
• [6] Bcl? associated athanogene 4 promotes proliferation, migration and invasion of gastric cancer cells.Mol Med Rep. 2017 Oct;16(4):3753-3760. doi: 10.3892/mmr.2017.7073. Epub 2017 Jul 21.
• [7] Detection of Known and Novel FGFR Fusions in Non-Small Cell Lung Cancer by Comprehensive Genomic Profiling.J Thorac Oncol. 2019 Jan;14(1):54-62. doi: 10.1016/j.jtho.2018.09.014. Epub 2018 Sep 26.
• [8] MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD).J Invest Dermatol. 2013 May;133(5):1286-93. doi: 10.1038/jid.2012.400. Epub 2012 Nov 29.
• [9] Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis.Neurobiol Dis. 2005 Apr;18(3):537-50. doi: 10.1016/j.nbd.2004.10.007.
• [10] Expression of Bcl-2 and the antiapoptotic BAG family proteins in ovarian cancer.Appl Immunohistochem Mol Morphol. 2013 Dec;21(6):518-24. doi: 10.1097/PAI.0b013e318284a053.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] 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.
• [14] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [15] 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.
• [16] 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.
• [17] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [18] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [19] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [20] 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.
• [21] 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.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [23] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
• [24] The anti-apoptotic activity of BAG3 is restricted by caspases and the proteasome. PLoS One. 2009;4(4):e5136. doi: 10.1371/journal.pone.0005136. Epub 2009 Apr 8.