Development of Glucose Regularted Protein 94-Selective Inhibitors Based on the Bnlm and Radamide Scaffold
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Issue Date
2016-04-14Author
Crowley, Vincent M.
Khandelwal, Anuj
Mishra, Sanket J.
Stothert, Andrew R.
Huard, Dustin J. E.
Zhao, Jinbo
Muth, Aaron
Duerfeldt, Adam S.
Kizziah, James L.
Lieberman, Raquel L.
Dickey, Chad A.
Blagg, Brian S. J.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jmedchem.6b00085.
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Show full item recordAbstract
Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.
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Citation
Crowley, V. M., Khandelwal, A., Mishra, S., Stothert, A. R., Huard, D. J. E., Zhao, J., … Blagg, B. S. J. (2016). Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold. Journal of Medicinal Chemistry, 59(7), 3471–3488. http://doi.org/10.1021/acs.jmedchem.6b00085
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