Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJI2RCI)

• DOT Name: Heat shock cognate 71 kDa protein (HSPA8)
• Synonyms: EC 3.6.4.10; Heat shock 70 kDa protein 8; Lipopolysaccharide-associated protein 1; LAP-1; LPS-associated protein 1
• Gene Name: HSPA8
• UniProt ID: HSP7C_HUMAN
• PDB ID: 3AGY ; 3AGZ ; 3ESK ; 3FZF ; 3FZH ; 3FZK ; 3FZL ; 3FZM ; 3LDQ ; 3M3Z ; 4H5N ; 4H5R ; 4H5T ; 4H5V ; 4H5W ; 4HWI ; 4KBQ ; 5AQF ; 5AQG ; 5AQH ; 5AQI ; 5AQJ ; 5AQK ; 5AQL ; 5AQM ; 5AQN ; 5AQO ; 5AQP ; 5AQQ ; 5AQR ; 5AQS ; 5AQT ; 5AQU ; 5AQV ; 6B1I ; 6B1M ; 6B1N ; 6ZYJ
• EC Number: 3.6.4.10
• Pfam ID: PF00012
• Sequence:
  MSKGPAVGIDLGTTYSCVGVFQHGKVEIIANDQGNRTTPSYVAFTDTERLIGDAAKNQVA
  MNPTNTVFDAKRLIGRRFDDAVVQSDMKHWPFMVVNDAGRPKVQVEYKGETKSFYPEEVS
  SMVLTKMKEIAEAYLGKTVTNAVVTVPAYFNDSQRQATKDAGTIAGLNVLRIINEPTAAA
  IAYGLDKKVGAERNVLIFDLGGGTFDVSILTIEDGIFEVKSTAGDTHLGGEDFDNRMVNH
  FIAEFKRKHKKDISENKRAVRRLRTACERAKRTLSSSTQASIEIDSLYEGIDFYTSITRA
  RFEELNADLFRGTLDPVEKALRDAKLDKSQIHDIVLVGGSTRIPKIQKLLQDFFNGKELN
  KSINPDEAVAYGAAVQAAILSGDKSENVQDLLLLDVTPLSLGIETAGGVMTVLIKRNTTI
  PTKQTQTFTTYSDNQPGVLIQVYEGERAMTKDNNLLGKFELTGIPPAPRGVPQIEVTFDI
  DANGILNVSAVDKSTGKENKITITNDKGRLSKEDIERMVQEAEKYKAEDEKQRDKVSSKN
  SLESYAFNMKATVEDEKLQGKINDEDKQKILDKCNEIINWLDKNQTAEKEEFEHQQKELE
  KVCNPIITKLYQSAGGMPGGMPGGFPGGGAPPSGGASSGPTIEEVD
• Function: Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, chaperone-mediated autophagy, activation of proteolysis of misfolded proteins, formation and dissociation of protein complexes, and antigen presentation. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation. The affinity of HSP70 for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J-domain co-chaperones HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1. Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70. Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes. Substrate recognition component in chaperone-mediated autophagy (CMA), a selective protein degradation process that mediates degradation of proteins with a -KFERQ motif: HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. KFERQ motif-containing proteins are eventually transported into the lysosomal lumen where they are degraded. In conjunction with LAMP2, facilitates MHC class II presentation of cytoplasmic antigens by guiding antigens to the lysosomal membrane for interaction with LAMP2 which then elicits MHC class II presentation of peptides to the cell membrane. Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1. It is recruited to clathrin-coated vesicles through its interaction with DNAJC6 leading to activation of HSPA8/HSC70 ATPase activity and therefore uncoating of clathrin-coated vesicles.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Spliceosome (hsa03040)
  MAPK sig.ling pathway (hsa04010)
  Protein processing in endoplasmic reticulum (hsa04141)
  Endocytosis (hsa04144)
  Longevity regulating pathway - multiple species (hsa04213)
  Antigen processing and presentation (hsa04612)
  Estrogen sig.ling pathway (hsa04915)
  Prion disease (hsa05020)
  Legionellosis (hsa05134)
  Toxoplasmosis (hsa05145)
  Measles (hsa05162)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  Attenuation phase (R-HSA-3371568)
  HSF1-dependent transactivation (R-HSA-3371571)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  CHL1 interactions (R-HSA-447041)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Neutrophil degranulation (R-HSA-6798695)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Protein methylation (R-HSA-8876725)
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  Lipophagy (R-HSA-9613354)
  Chaperone Mediated Autophagy (R-HSA-9613829)
  Late endosomal microautophagy (R-HSA-9615710)
  PKR-mediated signaling (R-HSA-9833482)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Heat shock cognate 71 kDa protein (HSPA8) affects the response to substance of Fluorouracil.	[49]
Cyclophosphamide	DM4O2Z7	Approved	Heat shock cognate 71 kDa protein (HSPA8) affects the response to substance of Cyclophosphamide.	[49]

42 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 Heat shock cognate 71 kDa protein (HSPA8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Heat shock cognate 71 kDa protein (HSPA8).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[18]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[19]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[22]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[22]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[23]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[25]
Etretinate	DM2CZFA	Approved	Etretinate decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[27]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[35]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[37]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[38]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[39]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[40]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[41]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Heat shock cognate 71 kDa protein (HSPA8).	[42]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[44]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[45]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[46]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[47]
Pyrrolidine dithiocarbamate	DM5ZAS6	Investigative	Pyrrolidine dithiocarbamate increases the expression of Heat shock cognate 71 kDa protein (HSPA8).	[48]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Heat shock cognate 71 kDa protein (HSPA8).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Heat shock cognate 71 kDa protein (HSPA8).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Heat shock cognate 71 kDa protein (HSPA8).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Dasatinib affects the binding of Heat shock cognate 71 kDa protein (HSPA8).	[20]
Indomethacin	DMSC4A7	Approved	Indomethacin affects the localization of Heat shock cognate 71 kDa protein (HSPA8).	[21]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the localization of Heat shock cognate 71 kDa protein (HSPA8).	[21]
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Heat shock cognate 71 kDa protein (HSPA8).	[24]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE affects the localization of Heat shock cognate 71 kDa protein (HSPA8).	[43]

2 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB increases the metabolism of Heat shock cognate 71 kDa protein (HSPA8).	[28]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the metabolism of Heat shock cognate 71 kDa protein (HSPA8).	[28]

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