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Development of Radamide Analogs as Grp94 Inhibitors
Muth, Aaron Crowley, Vincent M. Khandelwal, Anuj Mishra, Sanket J. Zhao, Jinbo Hall, Jessica Ann Blagg, Brian S. J.
Muth, Aaron
Crowley, Vincent M.
Khandelwal, Anuj
Mishra, Sanket J.
Zhao, Jinbo
Hall, Jessica Ann
Blagg, Brian S. J.
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Abstract
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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2014-08-01
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Elsevier
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Muth_Elsevier_2014.pdf
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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