IPI-504 (Retaspimycin hydrochloride) 是一种有效的 Hsp90 抑制剂，对 Hsp90 和 Grp9 的 EC50 均为 119 nM。
Retaspimycin hydrochloride (also known as IPI-504), a hydroquinone hydrochloride salt derivative of 17-AAG, is a novel, potent and selective inhibitor of heat shock protein 90(Hsp90) that binds to the amino-terminal ATP/ADP-binding site of Hsp90. As a highly water-soluble version of 17-AAG, IPI-504 (solubility > 200 mg/mL) does not need prior dissolution in organic solvents and hence can be delivered in high concentrations. Once in the systemic circulation, IPI-504 is deprotonated and converted into the free base IPI-504 which is subsequently oxidized to 17-AAG. IPI-504 potently inhibits proliferation in several tumor cell lines with 50% inhibition concentration IC50 values ranging from 10-40 nmol/L and has been used for the treatment of gastrointestinal stromal tumors, soft-tissue sarcomas and non-small cell lung cancer.
Reference
[1].Britt Erika Hanson and David H Vesole. Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent. Expert Opin. Investi. Drugs (2009) 18(9): 1375-1383
[2].David Siegel, Sundar Jagannath, David H. Vesole, Ivan Borello, Amitabha Mazumder, Constantine Mitsiades, Jill Goddard, Joi Dunbar, Emmanuel Normant, Julian Adams, David Grayzel, Kenneth C. Anderson and Paul Richardson. A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma. Leukemia & Lymphoma, 2011; 52(12): 2308-2315
[3].Ching Ching Leow, Jon Chesebrough, Karen T. Coffman, Christine A. Fazenbaker, John Gooya, David Weng, Steve Coats, Dowdy Jackson, Bahija Jallal and Yong Chang. Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2-positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib. Mol Cancer Ther 2009; 8: 2131-2141
| Cell experiment [1]: | |
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Cell lines |
Glioma cell lines (D-54 MG and U-251 MG cells) |
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Preparation method |
This compound was soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
1 or 2.5 μM; 24 or 48 hrs |
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Applications |
In glioma cells, IPI-504 inhibited cell proliferation through increasing sub-G1 population of cells and dose-dependently inducing fragmented DNA of the apoptotic cells. |
| Animal experiment [1]: | |
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Animal models |
Mice bearing human brain tumor D-54MG xenografts |
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Dosage form |
100 mg/kg; i.p.; b.i.d., twice weekly or 5/2/5 schedule (5 days on, 2 days off, and then 5 days on), for 6 weeks |
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Applications |
In immunocompromised mice, IPI-504 mildly attenuated tumor growth. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Di K, Keir ST, Alexandru-Abrams D, Gong X, Nguyen H, Friedman HS, Bota DA. Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models. J Neurooncol. 2014 Dec;120(3):473-81. | |
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