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Development of a Grp94 inhibitor
Duerfeldt, Adam S. Peterson, Laura B. Maynard, Jason C. Ng, Chun Leung Eletto, Davide Ostrovsky, Olga Shinogle, Heather E. Moore, David S. Argon, Yair Nicchitta, Christopher V.
Duerfeldt, Adam S.
Peterson, Laura B.
Maynard, Jason C.
Ng, Chun Leung
Eletto, Davide
Ostrovsky, Olga
Shinogle, Heather E.
Moore, David S.
Argon, Yair
Nicchitta, Christopher V.
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Abstract
Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/β (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/β client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.
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This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja303477g.
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2012-06-13
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American Chemical Society
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Duerfeldt, A. S., Peterson, L. B., Maynard, J. C., Ng, C. L., Eletto, D., Ostrovsky, O., … Blagg, B. S. J. (2012). Development of a Grp94 inhibitor. Journal of the American Chemical Society, 134(23), 9796–9804. http://doi.org/10.1021/ja303477g