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

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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3471-3488
Number of pages18
JournalJournal of medicinal chemistry
Volume59
Issue number7
DOIs
StatePublished - Apr 28 2016
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants from The National Institutes of Health to CA109265 (B.S.J.B.), EY024232 (B.S.J.B. and C.A.D.), and EY021205 (R.L.L.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grants (S10OD016360, S10RR024664) and NSF Major Research Instrumentation Grant (0320648).

Publisher Copyright:
© 2016 American Chemical Society.

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