Development of Radamide Analogs as Grp94 Inhibitors
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Issue Date
2014-08-01Author
Muth, Aaron
Crowley, Vincent M.
Khandelwal, Anuj
Mishra, Sanket J.
Zhao, Jinbo
Hall, Jessica Ann
Blagg, Brian S. J.
Publisher
Elsevier
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This article is made available under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND 3.0) License.
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Show full item recordAbstract
Hsp90 isoform-selective inhibition is highly desired as it can potentially avoid the toxic side-effects of pan-inhibition. The current study developed selective inhibitors of one such isoform, Grp94, predicated on the chimeric and pan-Hsp90 inhibitor, radamide (RDA). Replacement of the quinone moiety of RDA with a phenyl ring (2) was found to be better suited for Grp94 inhibition as it can fully interact with a unique hydrophobic pocket present in Grp94. An extensive SAR for this scaffold showed that substitutions at the 2- and 4-positions (8 and 27, respectively) manifested excellent Grp94 affinity and selectivity. Introduction of heteroatoms into the ring also proved beneficial, with a 2-pyridine derivative (38) exhibiting the highest Grp94 affinity (Kd = 820 nM). Subsequent cell-based assays showed that these Grp94 inhibitors inhibit migration of the metastatic breast cancer cell line, MDA-MB-231, as well as exhibit an anti-proliferative affect against the multiple myeloma cell line, RPMI 8226.
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Citation
Muth, A., Crowley, V., Khandelwal, A., Mishra, S., Zhao, J., Hall, J., & Blagg, B. S. J. (2014). Development of Radamide Analogs as Grp94 Inhibitors. Bioorganic & Medicinal Chemistry, 22(15), 4083–4098. http://doi.org/10.1016/j.bmc.2014.05.075
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