Development of a Grp94 inhibitor.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Duerfeldt, AS; Peterson, LB; Maynard, JC; Ng, CL; Eletto, D; Ostrovsky, O; Shinogle, HE; Moore, DS; Argon, Y; Nicchitta, CV; Blagg, BSJ

Published Date

  • June 13, 2012

Published In

Volume / Issue

  • 134 / 23

Start / End Page

  • 9796 - 9804

PubMed ID

  • 22642269

Pubmed Central ID

  • 22642269

Electronic International Standard Serial Number (EISSN)

  • 1520-5126

Digital Object Identifier (DOI)

  • 10.1021/ja303477g


  • eng

Conference Location

  • United States