Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT02XLBR)

• DOT Name: Endoplasmin (HSP90B1)
• Synonyms: 94 kDa glucose-regulated protein; GRP-94; Heat shock protein 90 kDa beta member 1; Tumor rejection antigen 1; gp96 homolog
• Gene Name: HSP90B1
• UniProt ID: ENPL_HUMAN
• PDB ID: 4NH9; 7ULL
• Pfam ID: PF13589 ; PF00183
• Sequence:
  MRALWVLGLCCVLLTFGSVRADDEVDVDGTVEEDLGKSREGSRTDDEVVQREEEAIQLDG
  LNASQIRELREKSEKFAFQAEVNRMMKLIINSLYKNKEIFLRELISNASDALDKIRLISL
  TDENALSGNEELTVKIKCDKEKNLLHVTDTGVGMTREELVKNLGTIAKSGTSEFLNKMTE
  AQEDGQSTSELIGQFGVGFYSAFLVADKVIVTSKHNNDTQHIWESDSNEFSVIADPRGNT
  LGRGTTITLVLKEEASDYLELDTIKNLVKKYSQFINFPIYVWSSKTETVEEPMEEEEAAK
  EEKEESDDEAAVEEEEEEKKPKTKKVEKTVWDWELMNDIKPIWQRPSKEVEEDEYKAFYK
  SFSKESDDPMAYIHFTAEGEVTFKSILFVPTSAPRGLFDEYGSKKSDYIKLYVRRVFITD
  DFHDMMPKYLNFVKGVVDSDDLPLNVSRETLQQHKLLKVIRKKLVRKTLDMIKKIADDKY
  NDTFWKEFGTNIKLGVIEDHSNRTRLAKLLRFQSSHHPTDITSLDQYVERMKEKQDKIYF
  MAGSSRKEAESSPFVERLLKKGYEVIYLTEPVDEYCIQALPEFDGKRFQNVAKEGVKFDE
  SEKTKESREAVEKEFEPLLNWMKDKALKDKIEKAVVSQRLTESPCALVASQYGWSGNMER
  IMKAQAYQTGKDISTNYYASQKKTFEINPRHPLIRDMLRRIKEDEDDKTVLDLAVVLFET
  ATLRSGYLLPDTKAYGDRIERMLRLSLNIDPDAKVEEEPEEEPEETAEDTTEDTEQDEDE
  EMDVGTDEEEETAKESTAEKDEL
• Function: Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors. Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity. May participate in the unfolding of cytosolic leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1 to facilitate their translocation into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and secretion; the translocation process is mediated by the cargo receptor TMED10.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  PI3K-Akt sig.ling pathway (hsa04151)
  IL-17 sig.ling pathway (hsa04657)
  Estrogen sig.ling pathway (hsa04915)
  Thyroid hormone synthesis (hsa04918)
  Salmonella infection (hsa05132)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Prostate cancer (hsa05215)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Scavenging by Class A Receptors (R-HSA-3000480)
  ATF6 (ATF6-alpha) activates chaperone genes (R-HSA-381183)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)

Molecular Interaction Atlas (MIA) of This DOT

36 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 Endoplasmin (HSP90B1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Endoplasmin (HSP90B1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endoplasmin (HSP90B1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endoplasmin (HSP90B1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Endoplasmin (HSP90B1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoplasmin (HSP90B1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Endoplasmin (HSP90B1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Endoplasmin (HSP90B1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Endoplasmin (HSP90B1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Endoplasmin (HSP90B1).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Endoplasmin (HSP90B1).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Endoplasmin (HSP90B1).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Endoplasmin (HSP90B1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Endoplasmin (HSP90B1).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Endoplasmin (HSP90B1).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Endoplasmin (HSP90B1).	[15]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Endoplasmin (HSP90B1).	[16]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Endoplasmin (HSP90B1).	[17]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Endoplasmin (HSP90B1).	[18]
Glucosamine	DM4ZLFD	Approved	Glucosamine increases the expression of Endoplasmin (HSP90B1).	[19]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose increases the expression of Endoplasmin (HSP90B1).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Endoplasmin (HSP90B1).	[21]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Endoplasmin (HSP90B1).	[2]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Endoplasmin (HSP90B1).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Endoplasmin (HSP90B1).	[23]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Endoplasmin (HSP90B1).	[11]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Endoplasmin (HSP90B1).	[5]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Endoplasmin (HSP90B1).	[26]
5-(N,N-hexamethylene)-amiloride	DMC4IUQ	Preclinical	5-(N,N-hexamethylene)-amiloride affects the expression of Endoplasmin (HSP90B1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Endoplasmin (HSP90B1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Endoplasmin (HSP90B1).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Endoplasmin (HSP90B1).	[30]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Endoplasmin (HSP90B1).	[31]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Endoplasmin (HSP90B1).	[32]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Endoplasmin (HSP90B1).	[34]
SNX-2112	DMB5A80	Investigative	SNX-2112 decreases the expression of Endoplasmin (HSP90B1).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Endoplasmin (HSP90B1).	[24]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin affects the binding of Endoplasmin (HSP90B1).	[25]
D-glucose	DMMG2TO	Investigative	D-glucose increases the secretion of Endoplasmin (HSP90B1).	[33]

References

• [1] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [2] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [6] 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.
• [7] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [15] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [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] A comparative proteomic analysis for capsaicin-induced apoptosis between human hepatocarcinoma (HepG2) and human neuroblastoma (SK-N-SH) cells. Proteomics. 2008 Nov;8(22):4748-67. doi: 10.1002/pmic.200800094.
• [18] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [19] Glucosamine-induced endoplasmic reticulum stress promotes ApoB100 degradation: evidence for Grp78-mediated targeting to proteasomal degradation. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):571-7. doi: 10.1161/01.ATV.0000154142.61859.94. Epub 2004 Dec 23.
• [20] HHQ-4, a quinoline derivate, preferentially inhibits proliferation of glucose-deprived breast cancer cells as a GRP78 down-regulator. Toxicol Appl Pharmacol. 2019 Jun 15;373:10-25. doi: 10.1016/j.taap.2019.04.017. Epub 2019 Apr 22.
• [21] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [22] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [23] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [24] 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.
• [25] p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. J Biol Chem. 1996 Mar 1;271(9):4974-7. doi: 10.1074/jbc.271.9.4974.
• [26] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [27] Amiloride derivatives induce apoptosis by depleting ER Ca(2+) stores in vascular endothelial cells. Br J Pharmacol. 2009 Apr;156(8):1296-304.
• [28] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [29] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [32] 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.
• [33] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [34] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [35] The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-B and disruption of mitochondria-dependent pathways. Chem Biol Interact. 2013 Sep 5;205(1):1-10. doi: 10.1016/j.cbi.2013.06.007. Epub 2013 Jun 15.