Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Crowley, Vincent M.; Khandelwal, Anuj; Mishra, Sanket; 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.

doi:10.1021/acs.jmedchem.6b00085

Title: Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Journal Article · Mon Apr 04 00:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b00085· OSTI ID:1251219

Crowley, Vincent M. ^[1]; Khandelwal, Anuj ^[1]; Mishra, Sanket ^[1]; Stothert, Andrew R. ^[2]; Huard, Dustin J. E. ^[3]; Zhao, Jinbo ^[1]; Muth, Aaron ^[1]; Duerfeldt, Adam S. ^[1]; Kizziah, James L. ^[3]; Lieberman, Raquel L. ^[3]; Dickey, Chad A. ^[2]; Blagg, Brian S. J. ^[1]

Univ. of Kansas, Lawrence, KS (United States)
Univ. of South Florida, Tampa, FL (United States)
Georgia Inst. of Technology, Atlanta, GA (United States)

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. Furthermore, 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: CA109265; EY024232; EY021205; S10OD016360; S10RR024664; 0320648

OSTI ID:: 1251219

Journal Information:: Journal of Medicinal Chemistry, Vol. 59, Issue 7; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 48 works

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