Second Generation Grp94‐Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer
Year: 2017
Type: article
Abstract: Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure-activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.
Source: Chemistry - A European Journal
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: New paradigms for Hsp90 inhibition, Avance II 500 High Performance Digital NMR Spectrometer System, AVIII HD 400 NMR spectrometer to replace existing DRX 400, Grp94-selective inhibitors to treat heredity glaucoma, G5099715671, The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors, Characterization of purified myocilin: glaucoma as a protein misfolding disease, G958486678
OpenAlex ID: W2751190598