Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT78R5H)

• DTT Name: Heat shock protein 90 alpha (HSP90A)
• Synonyms: Renal carcinoma antigen NY-REN-38; Lipopolysaccharide-associated protein 2; LPS-associated protein 2; LAP-2; Heat shock protein HSP 90-alpha; Heat shock 86 kDa; HSPCA; HSPC1; HSP90A; HSP86; HSP 86
• Gene Name: HSP90AA1
• DTT Type: Successful target; [1]
• BioChemical Class: Heat shock protein
• UniProt ID: HS90A_HUMAN
• TTD ID: T18477
• Sequence:
  MPEETQTQDQPMEEEEVETFAFQAEIAQLMSLIINTFYSNKEIFLRELISNSSDALDKIR
  YESLTDPSKLDSGKELHINLIPNKQDRTLTIVDTGIGMTKADLINNLGTIAKSGTKAFME
  ALQAGADISMIGQFGVGFYSAYLVAEKVTVITKHNDDEQYAWESSAGGSFTVRTDTGEPM
  GRGTKVILHLKEDQTEYLEERRIKEIVKKHSQFIGYPITLFVEKERDKEVSDDEAEEKED
  KEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEELNKTKPIWTRN
  PDDITNEEYGEFYKSLTNDWEDHLAVKHFSVEGQLEFRALLFVPRRAPFDLFENRKKKNN
  IKLYVRRVFIMDNCEELIPEYLNFIRGVVDSEDLPLNISREMLQQSKILKVIRKNLVKKC
  LELFTELAEDKENYKKFYEQFSKNIKLGIHEDSQNRKKLSELLRYYTSASGDEMVSLKDY
  CTRMKENQKHIYYITGETKDQVANSAFVERLRKHGLEVIYMIEPIDEYCVQQLKEFEGKT
  LVSVTKEGLELPEDEEEKKKQEEKKTKFENLCKIMKDILEKKVEKVVVSNRLVTSPCCIV
  TSTYGWTANMERIMKAQALRDNSTMGYMAAKKHLEINPDHSIIETLRQKAEADKNDKSVK
  DLVILLYETALLSSGFSLEDPQTHANRIYRMIKLGLGIDEDDPTADDTSAAVTEEMPPLE
  GDDDTSRMEEVD
• Function: Undergoes a functional cycle that is linked to its ATPase activity which is essential for its chaperone 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. Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle. Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues(). Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes. Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation. 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.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  PI3K-Akt signaling pathway (hsa04151)
  Antigen processing and presentation (hsa04612)
  NOD-like receptor signaling pathway (hsa04621)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Pathways in cancer (hsa05200)
  Prostate cancer (hsa05215)
• Reactome Pathway:
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  eNOS activation (R-HSA-203615)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Attenuation phase (R-HSA-3371568)
  HSF1-dependent transactivation (R-HSA-3371571)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization?from the centrosome (R-HSA-380284)
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  Constitutive Signaling by EGFRvIII (R-HSA-5637810)
  Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amlexanox	DM0DQM5	Respiratory tract inflammation	CA07	Approved	[2]
Cromoglicate	DM74LZK	Asthma	CA23	Approved	[2]

14 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BIIB-021	DMPAJ41	Breast cancer	2C60-2C65	Phase 2	[3]
Efungumab	DMBHP56	Breast cancer	2C60-2C65	Phase 2	[4]
KW-2478	DMJGL72	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
NVP-AUY922	DMTYXQF	Multiple myeloma	2A83	Phase 2	[6]
Tanespimycin	DMNLQHK	Breast cancer	2C60-2C65	Phase 2	[1]
VER 50589	DMFLZPC	Breast cancer	2C60-2C65	Phase 2	[6]
SNX-5422	DMIU0VP	Haematological malignancy	2B33.Y	Phase 1/2	[7]
Alvespimycin hydrochloride	DM6KU93	Ovarian cancer	2C73	Phase 1	[8]
AT13387	DM2B9E0	Melanoma	2C30	Phase 1	[9]
BIIB 028	DMTRF71	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
Debio 0932	DMWP3G1	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
PU-AD	DMKSU35	Encephalopathy	8E47	Phase 1	[12]
PU3	DMJO0BP	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
RTA-901	DM7C062	Diabetic neuropathy	8C0Z	Phase 1	[12]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HBP-347	DMX3IRE	Autoimmune diabetes	5A10	Discontinued in Phase 3	[13]
Geldanamycin	DMS7TC5	Kidney cancer	2C90.0	Discontinued in Phase 2	[14]
IPI-493	DMCF0XK	Gastric adenocarcinoma	2B72	Discontinued in Phase 1	[15]
EC-154	DM5ITJF	Solid tumour/cancer	2A00-2F9Z	Terminated	[17]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CCT-018159	DM065ZH	Solid tumour/cancer	2A00-2F9Z	Preclinical	[6]
KOS-2484	DMXY81K	Solid tumour/cancer	2A00-2F9Z	Preclinical	[16]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
17-desmethoxy-17-aminogeldanamycin	DMCALYO	Discovery agent	N.A.	Investigative	[18]
2-(1H-pyrrol-1-ylcarbonyl)benzene-1,3,5-triol	DMUY75A	Discovery agent	N.A.	Investigative	[19]
2-Methyl-2,4-Pentanediol	DMD45CU	Discovery agent	N.A.	Investigative	[20]
4-(2-methoxyethoxy)-6-methylpyrimidin-2-amine	DM9WQOJ	Discovery agent	N.A.	Investigative	[19]
6-(3-BROMO-2-NAPHTHYL)-1,3,5-TRIAZINE-2,4-DIAMINE	DM89LF5	Discovery agent	N.A.	Investigative	[19]
8-BENZO[1,3]DIOXOL-,5-YLMETHYL-9-BUTYL-9H-	DMT8QAP	Discovery agent	N.A.	Investigative	[19]
9-Butyl-8-(3-Methoxybenzyl)-9h-Purin-6-Amine	DMXU90T	Discovery agent	N.A.	Investigative	[19]
9-Butyl-8-(4-Methoxybenzyl)-9h-Purin-6-Amine	DMKHPAE	Discovery agent	N.A.	Investigative	[19]
Geldanamycin-estradiol hybrid	DMUSJ96	Discovery agent	N.A.	Investigative	[21]
GNF-PF-67	DM3SYH5	Discovery agent	N.A.	Investigative	[22]
KOSN1559	DM1SKNP	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
Macbecin	DMDLF0J	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
PU24S	DMHAJC1	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
Radicicol	DMNZS94	Discovery agent	N.A.	Investigative	[23]
RHEIN	DMS6IJ0	Discovery agent	N.A.	Investigative	[22]
SNX-2112	DMB5A80	Discovery agent	N.A.	Investigative	[18]
VER-49009	DMF1KDX	Discovery agent	N.A.	Investigative	[24]
ZEARALANONE	DMI5WF1	Discovery agent	N.A.	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Ovarian cancer	2C82	Ovarian tissue	3.96E-01	0.18	0.48
Multiple myeloma	2C82	Bone marrow	5.98E-06	1.3	4.35
Melanoma	2C82	Skin	1.54E-02	0.44	0.71
Lung cancer	2C82	Lung tissue	4.65E-03	0.15	0.6

References

• [1] Tanespimycin: the opportunities and challenges of targeting heat shock protein 90. Expert Opin Investig Drugs. 2009 Jun;18(6):861-8.
• [2] Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox. Biochem J. 2003 Sep 1;374(Pt 2):433-41.
• [3] BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther. 2009 Apr;8(4):921-9.
• [4] Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother. 2009 Nov;43(11):1818-23.
• [5] Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib. Blood Cancer J. 2012 Apr;2(4):e68.
• [6] Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem. 2008 Oct;8(7):761-82.
• [7] SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hema... Blood. 2009 Jan 22;113(4):846-55.
• [8] Stage 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.
• [9] Astex Presents Updates on AT13387, its HSP90 Inhibitor, and AT9283, its Multi-Targeted Kinase Inhibitor at the EORTC-NCI-AACR Cancer Conference. Astex. 2008.
• [10] Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors. Clin Cancer Res. 2013 Sep 1;19(17):4824-31.
• [11] Clinical pipeline report, company report or official report of Debiopharm (2011).
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [13] US patent application no. 2013,0023,420, Susceptibility to hsp90-inhibitors.
• [14] Heat shock protein 90 regulates the stability of MEKK3 in HEK293 cells. Cell Immunol. 2009;259(1):49-55.
• [15] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [16] US patent application no. 2014,0079,636, Targeted therapeutics.
• [17] WO patent application no. 2013,1734,36, Pre-selection of subjects for therapeutic treatment with an hsp90 inhibitor based on hypoxic status.
• [18] Heat shock protein 90: inhibitors in clinical trials. J Med Chem. 2010 Jan 14;53(1):3-17.
• [19] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [20] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [21] Synthesis and evaluation of geldanamycin-estradiol hybrids. Bioorg Med Chem Lett. 1999 May 3;9(9):1233-8.
• [22] 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.
• [23] High-throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity. Anal Biochem. 2004 Apr 15;327(2):176-83.
• [24] Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem. 2005 Jun 30;48(13):4212-5.