17-AAG

• CAT Number: I004806
• CAS Number: 75747-14-7
• Molecular Formula: C₃₁H₄₃N₃O₈
• Molecular Weight: 585.69
• Purity: ≥95%
• Synonyms: Tanespimycin;17-AAG; KOS-953; [(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-21-(prop-2-enylamino)-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate
• Target: HSP
• Solubility: DMSO: ≥ 55 mg/mL
• Storage: Store at 4°C
• IC50: 5 nM
• IUPAC Name: [(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-19-(prop-2-enylamino)-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• InChI: InChI=1S/C31H43N3O8/c1-8-12-33-26-21-13-17(2)14-25(41-7)27(36)19(4)15-20(5)29(42-31(32)39)24(40-6)11-9-10-18(3)30(38)34-22(28(21)37)16-23(26)35/h8-11,15-17,19,24-25,27,29,33,36H,1,12-14H2,2-7H3,(H2,32,39)(H,34,38)/b11-9-,18-10+,20-15+/t17-,19+,24+,25+,27-,29+/m1/s1
• InChIKey: AYUNIORJHRXIBJ-TXHRRWQRSA-N
• SMILES: C[C@H]1C[C@@H]([C@@H]([C@H](/C=C(/[C@@H]([C@H](/C=C\C=C(\C(=O)NC2=CC(=O)C(=C(C1)C2=O)NCC=C)/C)OC)OC(=O)N)\C)C)O)OC

17-AAG (17-allylamino-17-demethoxygeldanamycin)(Cat No.:I004806) is a synthetic derivative of geldanamycin and a potent inhibitor of heat shock protein 90 (Hsp90). Hsp90 is a chaperone protein involved in the folding and stabilization of numerous client proteins, many of which are critical for cell growth and survival. By inhibiting Hsp90, 17-AAG disrupts the proper folding and function of client proteins, leading to degradation and/or inhibition of their activity. This can result in the inhibition of multiple signaling pathways involved in cell proliferation, survival, and angiogenesis. 17-AAG has shown promise as an anticancer agent and is being investigated in clinical trials for various types of cancer.

Overview of Clinical Research

Originator: National Institutes of Health (USA)
Developer: Kosan Biosciences
Class: Antineoplastics; Benzoquinones; Cytostatic antibiotics; Macrocyclic lactams; Small molecules
Mechanism of Action: HSP90 heat-shock protein inhibitors
Orphan Drug Status: Yes – Multiple myeloma

New Molecular Entity: Yes

Highest Development Phases: Discontinued Breast cancer;

Reference

1. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):17-22. doi: 10.3816/CLML.2011.n.002.
Tanespimycin as antitumor therapy.
Dimopoulos MA(1), Mitsiades CS, Anderson KC, Richardson PG.
Author information:
(1)Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.
BACKGROUND: The 90 kDa heat shock protein (HSP90), which facilitates proper folding and stability of numerous signaling molecules involved in growth control, cell survival, and development, has been implicated in malignant processes. Like its parent compound geldanamycin, tanespimycin binds to HSP90 and causes antineoplastic effects in vitro and in vivo.
MATERIALS AND METHODS: All relevant published papers identified through searches of PubMed and abstracts from major recent hematology and oncology meetings were reviewed as of October 2009.
RESULTS: Different formulations and schedules of tanespimycin monotherapy and combination therapy have been tested in several phase I studies in patients with solid tumors or multiple myeloma (MM). No responses have been reported in studies of tanespimycin monotherapy in patients with metastatic melanoma. Tanespimycin given in combination with trastuzumab in patients with metastatic breast cancer induced a partial response in 24% of patients. Single-agent tanespimycin showed activity in MM and in combination with bortezomib, 27% of patients achieved minor response or better (48% bortezomib-naive patients, 22% bortezomib-pretreated patients, 13% bortezomib-refractory patients). CONCLUSION: Tanespimycin represents a promising new agent for the treatment of relapsed/refractory MM. Results of ongoing and future trials will determine the role of tanespimycin both in MM and other malignancies, including breast cancer.
2. Expert Opin Investig Drugs. 2009 Jun;18(6):861-8. doi: 10.1517/13543780902953699.
Tanespimycin: the opportunities and challenges of targeting heat shock protein 90.
Erlichman C(1).
Author information:
(1)Department of Oncology, Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN 55905, USA.
BACKGROUND: Heat shock protein 90 (HSP90) is the core of a multi-chaperone complex critical for the folding, trafficking, and stabilization of many client proteins that are involved in tumor cell proliferation, survival, and angiogenesis. Targeting HSP90 results in degradation of these client proteins. OBJECTIVE: Data supporting the development of tanespimycin, which targets HSP90, are reviewed.
METHODS: Clinical data available for tanespimycin development are presented. RESULTS: Tanespimycin can be given safely at biologically active doses with mild toxicity such as nausea, vomiting, diarrhea, and fatigue. Although single-agent studies have shown limited activity, combinations of tanespimycin with bortezomib or trastuzumab have suggested promising avenues of further evaluation in multiple myeloma and breast cancer, respectively.
CONCLUSIONS: Further development of HSP90-targeted strategies include testing of novel chemical structures having better solubility and stability and the potential for oral administration. Targeting of HSP90 in combination with other heat shock proteins, such as HSP70 or HSP27, may be an alternative strategy that warrants further exploration.