Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTHYBIX)

• DTT Name: Heat shock protein 70 (HSP70)
• Synonyms: Heat shock 70 kDa protein; HSP72; HSP70
• Gene Name: HSPA1A
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Heat shock protein
• UniProt ID: HS71A_HUMAN ; HS71B_HUMAN
• TTD ID: T49639
• Sequence:
  MAKAAAIGIDLGTTYSCVGVFQHGKVEIIANDQGNRTTPSYVAFTDTERLIGDAAKNQVA
  LNPQNTVFDAKRLIGRKFGDPVVQSDMKHWPFQVINDGDKPKVQVSYKGETKAFYPEEIS
  SMVLTKMKEIAEAYLGYPVTNAVITVPAYFNDSQRQATKDAGVIAGLNVLRIINEPTAAA
  IAYGLDRTGKGERNVLIFDLGGGTFDVSILTIDDGIFEVKATAGDTHLGGEDFDNRLVNH
  FVEEFKRKHKKDISQNKRAVRRLRTACERAKRTLSSSTQASLEIDSLFEGIDFYTSITRA
  RFEELCSDLFRSTLEPVEKALRDAKLDKAQIHDLVLVGGSTRIPKVQKLLQDFFNGRDLN
  KSINPDEAVAYGAAVQAAILMGDKSENVQDLLLLDVAPLSLGLETAGGVMTALIKRNSTI
  PTKQTQIFTTYSDNQPGVLIQVYEGERAMTKDNNLLGRFELSGIPPAPRGVPQIEVTFDI
  DANGILNVTATDKSTGKANKITITNDKGRLSKEEIERMVQEAEKYKAEDEVQRERVSAKN
  ALESYAFNMKSAVEDEGLKGKISEADKKKVLDKCQEVISWLDANTLAEKDEFEHKRKELE
  QVCNPIISGLYQGAGGPGPGGFGAQGPKGGSGSGPTIEEVD
• Function: In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form. Upon exposure to heat and other stress stimuli, undergoes homotrimerization and activates HSP gene transcription through binding to site-specific heat shock elements (HSEs) present in the promoter regions of HSP genes. Activation is reversible, and during the attenuation and recovery phase period of the HSR, returns to its unactivated form. Binds to inverted 5'-NGAAN-3' pentamer DNA sequences. Binds to chromatin at heat shock gene promoters. Plays also several other functions independently of its transcriptional activity. Involved in the repression of Ras-induced transcriptional activation of the c-fos gene in heat-stressed cells. Positively regulates pre-mRNA 3'-end processing and polyadenylation of HSP70 mRNA upon heat-stressed cells in a symplekin (SYMPK)-dependent manner. Plays a role in nuclear export of stress-induced HSP70 mRNA. Plays a role in the regulation of mitotic progression. Plays also a role as a negative regulator of non-homologous end joining (NHEJ) repair activity in a DNA damage-dependent manner. Involved in stress-induced cancer cell proliferation in a IER5-dependent manner. Function as a stress-inducible and DNA-binding transcription factor that plays a central role in the transcriptional activation of the heat shock response (HSR), leading to the expression of a large class of molecular chaperones heat shock proteins (HSPs) that protect cells from cellular insults' damage.
• KEGG Pathway:
  Spliceosome (hsa03040)
  MAPK signaling pathway (hsa04010)
  Protein processing in endoplasmic reticulum (hsa04141)
  Endocytosis (hsa04144)
  Longevity regulating pathway - multiple species (hsa04213)
  Antigen processing and presentation (hsa04612)
  Estrogen signaling pathway (hsa04915)
  Prion disease (hsa05020)
  Legionellosis (hsa05134)
  Toxoplasmosis (hsa05145)
  Measles (hsa05162)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  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)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Neutrophil degranulation (R-HSA-6798695)
  Viral RNP Complexes in the Host Cell Nucleus (R-HSA-168330)

Molecular Interaction Atlas (MIA) of This DTT

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AEG-33773	DMSBLOU	Diabetic neuropathy	8C0Z	Phase 2	[1]
AG-858	DMNQ5T2	leukaemia	2A60-2B33	Phase 2	[2]
AG-707	DM7PLMJ	Herpes simplex virus infection	1F00	Phase 1	[3]
BRX-005	DMTDWIE	Diabetic foot ulcer	BD54	Phase 1	[4]
Enkastim-ev	DMGLHYU	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
H-103	DMRCHOU	Metastatic malignant neoplasm	2D50-2E09	Phase 1	[6]
Minnelide	DMDER9S	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
Minnelide 001	DM5VEN9	Gastric adenocarcinoma	2B72	Phase 1	[8]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bimoclomol	DMOP95G	Diabetic complication	5A2Y	Discontinued in Phase 2	[9]
NK-1001	DMZMQDN	Atrial fibrillation	BC81.3	Discontinued in Phase 2	[10]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ELLAGIC ACID	DMX8BS5	Discovery agent	N.A.	Investigative	[11]
NSC-119910	DMKHMS4	Cardiac failure	BD10-BD13	Investigative	[11]
NSC-119911	DM1MRFW	Discovery agent	N.A.	Investigative	[11]
NSC-119913	DMVE69Y	Discovery agent	N.A.	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	1.03E-20	0.32	1.2
Gastric cancer	2C82	Gastric tissue	2.62E-01	-4.07E-03	-0.01

References

• [1] Mitogen-activated protein kinase kinase kinase 12 (MAP3K12; DLK); c-jun N-terminal kinase (JNK). SciBX 2(11); doi:10.1038/scibx.2009.462. March 19 2009
• [2] Preparation of a Heat Shock Proteins 70-based Vaccine from DC-tumor fusion cells. Methods Mol Biol. 2011; 787: 255-265.
• [3] A heat shock protein based polyvalent vaccine targeting HSV-2: CD4(+) and CD8(+) cellular immunity and protective efficacy. Vaccine. 2011 Nov 3;29(47):8530-41.
• [4] Cardiovascular effects of BRX-005 comparison to bimoclomol. Life Sci. 2000 Aug 25;67(14):1783-9.
• [5] Company report (Multimmune)
• [6] A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. Gene Ther. 2009 Mar;16(3):376-82.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [9] Bimoclomol elevates heat shock protein 70 and cytoprotects rat neonatal cardiomyocytes. Eur J Pharmacol. 2002 Jan 18;435(1):73-7.
• [10] Novel therapeutic targets in the management of atrial fibrillation. Am J Cardiovasc Drugs. 2014 Dec;14(6):403-21.
• [11] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.