Conformationally Restricted Grp94-Selective Inhibitors

Selective inhibition of glucose regulated protein 94 (Grp94), the most structurally unique isoform of heat shock protein 90 (HSP90), has been implicated in the treatment of various disease states, including primary open-angle glaucoma and metastatic Cancer. In this study, nine analogues were designed and synthesized by conformationally restricting KUNG65, a second generation Grp94-selective inhibitor. Conformational constraints were applied to restrict the rotatable bonds and to bias the benzyl moiety into the Grp94 site 1 pocket as well as to reduce the entropic penalty paid upon binding. A fluorescence polarization assay demonstrated that lead compound C6 exhibited an affinity of 5.52 μM for Grp94 and showed no affinity for Hsp90α, indicating its potential as a Grp94-selective inhibitor.