Development of a Grp94 inhibitor

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

来源：Journal of the American Chemical Society, 2012, 134(23): 9796-9804.

DOI：10.1021/ja303477g

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 Hsp90 alpha/beta (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 Hsp90 alpha/beta client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.

• 出版日期2012-6-13