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