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Development of a Grp94 inhibitor
dc.contributor.author | Duerfeldt, Adam S. | |
dc.contributor.author | Peterson, Laura B. | |
dc.contributor.author | Maynard, Jason C. | |
dc.contributor.author | Ng, Chun Leung | |
dc.contributor.author | Eletto, Davide | |
dc.contributor.author | Ostrovsky, Olga | |
dc.contributor.author | Shinogle, Heather E. | |
dc.contributor.author | Moore, David S. | |
dc.contributor.author | Argon, Yair | |
dc.contributor.author | Nicchitta, Christopher V. | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.date.accessioned | 2017-06-05T20:02:59Z | |
dc.date.available | 2017-06-05T20:02:59Z | |
dc.date.issued | 2012-06-13 | |
dc.identifier.citation | 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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/24375 | |
dc.description | 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. | en_US |
dc.description.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. | en_US |
dc.publisher | American Chemical Society | en_US |
dc.title | Development of a Grp94 inhibitor | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Duerfeldt, Adam S. | |
kusw.kuauthor | Peterson, Laura B. | |
kusw.kuauthor | Shinogle, Heather E. | |
kusw.kuauthor | Moore, David S. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1021/ja303477g | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-3130-9890 | |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC3414055 | en_US |
dc.rights.accessrights | openAccess |