Development of a Grp94 inhibitor

摘要: 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 toxicities observed. These detriments may be consequence pan-Hsp90 inhibition, all clinically evaluated Hsp90 inhibitors simultaneously disrupt four human isoforms. Using structure-based approach, we designed an inhibitor Grp94, ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 Hsp90α/β (cytosolic isoforms) clients were investigated. Compound prevented intracellular trafficking Toll receptor, inhibited secretion IGF-II, affected conformation suppressed Drosophila larval growth, Grp94-dependent processes. In contrast, had no cell viability or cytosolic client proteins at similar concentrations. design, synthesis, evaluation are described herein.