1. Pharmaceutical development of IPI-504, an Hsp90 inhibitor and clinical candidate for the treatment of cancer
- Author
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John Lee, Roger H. Pak, Louis Grenier, Vince Ammoscato, Michael Curtis, Kaiming Li, John Henderson, Matthew Campbell, Denise Mayes, Jason Kropp, Natalie Goltz, Bennett Carter, Johan Sebastian Basuki, Bradley Maurer, Gary Baker, James R. Wright, David Rusch, Rebecca Ahn, Brian C. Austad, Kris Depew, Joseph Helble, Jie Ge, Jason J. Piotrowski, Marlene R. Booth, Julian Adams, Mark Douglas, Steven G. Wong, Laila Kott, James R. Porter, Geoff E. Sylvester, Dumitru Ionescu, Jennifer R. Porter, and Brendan Arsenault
- Subjects
Drug ,Hydroquinone ,Hydrochloride ,media_common.quotation_subject ,Cancer ,Pharmacology ,medicine.disease ,Hsp90 inhibitor ,Quinone ,Clinical trial ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,medicine ,media_common - Abstract
IPI-504 (retaspimycin hydrochloride) is an Hsp90 inhibitor that is the subject of multiple clinical trials for the treatment of cancer. IPI-504 is an aqueous soluble (>200 mg/ml) hydroquinone hydrochloride salt of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a quinone derivative also undergoing clinical evaluation, albeit with suboptimal formulations that address its inferior aqueous solubility (∼50 µg/ml). IPI-504 interconverts with 17-AAG in vivo through oxidation-reduction reactions that result in a dynamic redox equilibrium. The development challenges associated with redox active molecules are significant due to the pH, oxygen, and temperature sensitivities associated with such chemotypes. The API and sterile drug product manufacturing processes thus warrant the monitoring and control of these key variables. Furthermore, the pharmaceutical development challenges associated with cancer agents that are often fast-tracked due to unmet medical needs mandate a rapid development cycle with associated regulatory hurdles. Drug Dev Res 71: 429–438, 2010. © 2010 Wiley-Liss, Inc.
- Published
- 2010
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