Development of a Grp94 inhibitor

Adam S. Duerfeldt, Laura B. Peterson, Jason C. Maynard, Chun Leung Ng, Davide Eletto, Olga Ostrovsky, Heather E. Shinogle, David S. Moore, Yair Argon, Christopher V. Nicchitta, Brian S.J. Blagg

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/β (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/β client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.

Original languageEnglish (US)
Pages (from-to)9796-9804
Number of pages9
JournalJournal of the American Chemical Society
Volume134
Issue number23
DOIs
StatePublished - Jun 13 2012
Externally publishedYes

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