Target Information

Target General Infomation
Target ID
T18477
Former ID
TTDC00018
Target Name
Heat shock protein HSP 90
Gene Name
HSP90AA1
Synonyms
HSP 86; HSP90A; HSPC1; HSPCA; Renal carcinoma antigen NY-REN-38; HSP90AA1
Target Type
Clinical Trial
Disease Breast cancer; Melanoma [ICD9: 140-229, 172, 174, 175; ICD10: C00-C96, C43, C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Multiple myeloma [ICD9: 203; ICD10: C90]
Melanoma [ICD9: 172; ICD10: C43]
Ovarian cancer; Refractory hematological malignancies [ICD9: 140-229, 140-239, 183, 200-209; ICD10: C56, C81-C86]
Function
Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes.
BioChemical Class
Heat shock protein
Target Validation
T18477
UniProt ID
P07900
Sequence
MPEETQTQDQPMEEEEVETFAFQAEIAQLMSLIINTFYSNKEIFLRELISNSSDALDKIR
YESLTDPSKLDSGKELHINLIPNKQDRTLTIVDTGIGMTKADLINNLGTIAKSGTKAFME
ALQAGADISMIGQFGVGFYSAYLVAEKVTVITKHNDDEQYAWESSAGGSFTVRTDTGEPM
GRGTKVILHLKEDQTEYLEERRIKEIVKKHSQFIGYPITLFVEKERDKEVSDDEAEEKED
KEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEELNKTKPIWTRN
PDDITNEEYGEFYKSLTNDWEDHLAVKHFSVEGQLEFRALLFVPRRAPFDLFENRKKKNN
IKLYVRRVFIMDNCEELIPEYLNFIRGVVDSEDLPLNISREMLQQSKILKVIRKNLVKKC
LELFTELAEDKENYKKFYEQFSKNIKLGIHEDSQNRKKLSELLRYYTSASGDEMVSLKDY
CTRMKENQKHIYYITGETKDQVANSAFVERLRKHGLEVIYMIEPIDEYCVQQLKEFEGKT
LVSVTKEGLELPEDEEEKKKQEEKKTKFENLCKIMKDILEKKVEKVVVSNRLVTSPCCIV
TSTYGWTANMERIMKAQALRDNSTMGYMAAKKHLEINPDHSIIETLRQKAEADKNDKSVK
DLVILLYETALLSSGFSLEDPQTHANRIYRMIKLGLGIDEDDPTADDTSAAVTEEMPPLE
GDDDTSRMEEVD
Drugs and Mode of Action
Drug(s) Tanespimycin Drug Info Phase 2 Breast cancer; Melanoma [537114], [542715]
SNX-5422 Drug Info Phase 1/2 Cancer [548569]
Alvespimycin hydrochloride Drug Info Phase 1 Ovarian cancer; Refractory hematological malignancies [521606]
AT13387 Drug Info Phase 1 Melanoma [550300]
SNX-5422 Drug Info Phase 1 Hematological malignancies [548569]
Tanespimycin Drug Info Discontinued in Phase 3 Multiple myeloma [537114], [542715]
Inhibitor 2-(1H-pyrrol-1-ylcarbonyl)benzene-1,3,5-triol Drug Info [551374]
2-Methyl-2,4-Pentanediol Drug Info [551393]
4-(2-methoxyethoxy)-6-methylpyrimidin-2-amine Drug Info [551374]
6-(3-BROMO-2-NAPHTHYL)-1,3,5-TRIAZINE-2,4-DIAMINE Drug Info [551374]
8-BENZO[1,3]DIOXOL-,5-YLMETHYL-9-BUTYL-9H- Drug Info [551374]
9-Butyl-8-(3-Methoxybenzyl)-9h-Purin-6-Amine Drug Info [551374]
9-Butyl-8-(4-Methoxybenzyl)-9h-Purin-6-Amine Drug Info [551374]
Adenosine-5'-Diphosphate Drug Info [551391]
Alvespimycin hydrochloride Drug Info [536622], [536886], [537368]
AT13387 Drug Info [550608]
Geldanamycin-estradiol hybrid Drug Info [525501]
GNF-PF-67 Drug Info [531262]
RHEIN Drug Info [531262]
SNX-5422 Drug Info [536786], [536899]
Tanespimycin Drug Info [536786], [536886], [537107], [537374]
VER-49009 Drug Info [527601]
ZEARALANONE Drug Info [531262]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Protein processing in endoplasmic reticulum
PI3K-Akt signaling pathway
Antigen processing and presentation
NOD-like receptor signaling pathway
Progesterone-mediated oocyte maturation
Estrogen signaling pathway
Pathways in cancer
Prostate cancer
NetPath Pathway IL2 Signaling Pathway
TCR Signaling Pathway
Pathway Interaction Database Signaling events mediated by HDAC Class II
Validated targets of C-MYC transcriptional activation
Integrin-linked kinase signaling
LKB1 signaling events
Regulation of Telomerase
Glucocorticoid receptor regulatory network
Class I PI3K signaling events
IL2 signaling events mediated by PI3K
Regulation of Androgen receptor activity
Integrins in angiogenesis
Hypoxic and oxygen homeostasis regulation of HIF-1-alpha
ErbB receptor signaling network
VEGFR1 specific signals
Signaling events mediated by VEGFR1 and VEGFR2
Class I PI3K signaling events mediated by Akt
Reactome Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
Regulation of actin dynamics for phagocytic cup formation
eNOS activation
Regulation of PLK1 Activity at G2/M Transition
Attenuation phase
HSF1-dependent transactivation
Loss of Nlp from mitotic centrosomes
Recruitment of mitotic centrosome proteins and complexes
Loss of proteins required for interphase microtubule organization?from the centrosome
EPHA-mediated growth cone collapse
VEGFA-VEGFR2 Pathway
VEGFR2 mediated vascular permeability
Anchoring of the basal body to the plasma membrane
Constitutive Signaling by EGFRvIII
WikiPathways NRF2 pathway
Nuclear Receptors Meta-Pathway
Aryl Hydrocarbon Receptor Pathway
Binding and Uptake of Ligands by Scavenger Receptors
Signaling by ERBB2
Fcgamma receptor (FCGR) dependent phagocytosis
Influenza Life Cycle
EBV LMP1 signaling
Aryl Hydrocarbon Receptor
Corticotropin-releasing hormone
TNF alpha Signaling Pathway
Arylhydrocarbon receptor (AhR) signaling pathway
Signaling by EGFR
Semaphorin interactions
Mitotic G2-G2/M phases
Metabolism of nitric oxide
NOD pathway
References
Ref 521606ClinicalTrials.gov (NCT00089271) 17-DMAG in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphomas. U.S. National Institutes of Health.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 542715(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7751).
Ref 548569Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026704)
Ref 550300Clinical pipeline report, company report or official report of Astex Pharmaceuticals.
Ref 525501Bioorg Med Chem Lett. 1999 May 3;9(9):1233-8.Synthesis and evaluation of geldanamycin-estradiol hybrids.
Ref 527601J Med Chem. 2005 Jun 30;48(13):4212-5.Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.
Ref 531262Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6. Epub 2010 Oct 21.In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2).
Ref 536622Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Jul;51(1):34-41.
Ref 536786Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr Opin Pharmacol. 2008 Aug;8(4):370-4. Epub 2008 Jul 31.
Ref 536886Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem. 2008 Oct;8(7):761-82.
Ref 536899SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood. 2009 Jan 22;113(4):846-55. Epub 2008 Oct 23.
Ref 537107Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res. 2009 Mar 1;69(5):1966-75. Epub 2009 Feb 24.
Ref 537368Anti-proliferative activity of heat shock protein (Hsp) 90 inhibitors via beta-catenin/TCF7L2 pathway in adult T cell leukemia cells. Cancer Lett. 2009 May 20.
Ref 537374Tanespimycin: the opportunities and challenges of targeting heat shock protein 90. Expert Opin Investig Drugs. 2009 Jun;18(6):861-8.
Ref 550608Astex Presents Updates on AT13387, its HSP90 Inhibitor, and AT9283, its Multi-Targeted Kinase Inhibitor at the EORTC-NCI-AACR Cancer Conference. Astex. 2008.
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551391DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

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