This chapter deals with small molecule modulators of the refolding machinery centered around heat shock proteins (Hsps). They are designed to restore its impaired refolding capacity to rescue dysfunctional proteins, and to fight its pathological alterations in proteinopathies in general and in tauopathies in particular. Three key Hsp families are targeted in particular (either as such, or as members of chaperone–co-chaperone complexes) for therapeutic intervention against neurodegenerative diseases (NDDs): the small Hsp family, Hsp70, and Hsp90. Known modulators of each target (either by direct interaction with the Hsps, or by inhibition of chaperone–co-chaperone interactions, or by indirect control of their activation/expression/post-translational modification) are described in terms of their biological profile, and of their development potential as disease-modifying drugs against NDDs.

Targeting the Protein Quality Control (PQC) Machinery

Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

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

Pharmaceutical development of IPI-504, an Hsp90 inhibitor and clinical candidate for the treatment of cancer

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Pharmaceutical development of IPI-504, an Hsp90 inhibitor and clinical candidate for the treatment of cancer