Development of a Grp94 inhibitor
- 29 May 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 134 (23), 9796-9804
- https://doi.org/10.1021/ja303477g
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.Keywords
This publication has 70 references indexed in Scilit:
- GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulumBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Glucose regulated protein 94 is required for muscle differentiation through its control of the autocrine production of insulin-like growth factorsBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2010
- Grp94, the endoplasmic reticulum Hsp90, has a similar solution conformation to cytosolic Hsp90 in the absence of nucleotideProtein Science, 2009
- pH-Dependent Conformational Changes in Bacterial Hsp90 Reveal a Grp94-Like Conformation at pH 6 That Is Highly Active in Suppression of Citrate Synthase AggregationJournal of Molecular Biology, 2009
- Different Poses for Ligand and Chaperone in Inhibitor-Bound Hsp90 and GRP94: Implications for Paralog-Specific Drug DesignJournal of Molecular Biology, 2009
- New developments in Hsp90 inhibitors as anti-cancer therapeutics: Mechanisms, clinical perspective and more potentialDrug Resistance Updates, 2009
- Targeting Hsp90: small-molecule inhibitors and their clinical developmentCurrent Opinion in Pharmacology, 2008
- Structures of GRP94-Nucleotide Complexes Reveal Mechanistic Differences between the hsp90 ChaperonesMolecular Cell, 2007
- Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of MacrophagesImmunity, 2007