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Title: Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer

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.

Authors:
ORCiD logo [1];  [2];  [2]; ORCiD logo [3]
  1. Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr. Malott 4070 Lawrence KS 66045 USA
  2. School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta GA 30332 USA
  3. Warren Family Research Center for Drug Discovery and Development, and Department of Chemistry & Biochemistry, University of Notre Dame, 305 McCourtney Hall Notre Dame IN 46556 USA
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1409089
Resource Type:
Journal Article
Journal Name:
Chemistry - A European Journal
Additional Journal Information:
Journal Volume: 23; Journal Issue: 62; Journal ID: ISSN 0947-6539
Publisher:
ChemPubSoc Europe
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Crowley, Vincent M., Huard, Dustin J. E., Lieberman, Raquel L., and Blagg, Brian S. J. Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer. United States: N. p., 2017. Web. doi:10.1002/chem.201703398.
Crowley, Vincent M., Huard, Dustin J. E., Lieberman, Raquel L., & Blagg, Brian S. J. Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer. United States. doi:10.1002/chem.201703398.
Crowley, Vincent M., Huard, Dustin J. E., Lieberman, Raquel L., and Blagg, Brian S. J. Wed . "Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer". United States. doi:10.1002/chem.201703398.
@article{osti_1409089,
title = {Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer},
author = {Crowley, Vincent M. and Huard, Dustin J. E. and Lieberman, Raquel L. and Blagg, Brian S. J.},
abstractNote = {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.},
doi = {10.1002/chem.201703398},
journal = {Chemistry - A European Journal},
issn = {0947-6539},
number = 62,
volume = 23,
place = {United States},
year = {2017},
month = {9}
}

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