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Pharmaceutical development of IPI‐504, an Hsp90 inhibitor and clinical candidate for the treatment of cancer
Author(s) -
Porter James R.,
Adams Julian,
Ahn Rebecca,
Ammoscato Vince,
Arsenault Brendan,
Austad Brian C.,
Baker Gary,
Basuki Johan,
Booth Marlene R.,
Campbell Matthew J.,
Carter Bennett,
Curtis Michael,
Depew Kris,
Douglas Mark A.,
Ge Jie,
Grenier Louis,
Helble Joseph,
Henderson John,
Goltz Natalie,
Ionescu Dumitru,
Kott Laila,
Kropp Jason T.,
Lee John,
Li Kaiming,
Maurer Bradley,
Mayes Denise,
Pak Roger H.,
Piotrowski Jason,
Porter Jennifer R.,
Rusch David,
Sylvester Geoff E.,
Wong Steven,
Wright Jim
Publication year - 2010
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.20383
Subject(s) - chemistry , pharmacology , drug development , drug , in vivo , medicine , biology , microbiology and biotechnology
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.