dc.contributor.author | Muth, Aaron | |
dc.contributor.author | Crowley, Vincent M. | |
dc.contributor.author | Khandelwal, Anuj | |
dc.contributor.author | Mishra, Sanket J. | |
dc.contributor.author | Zhao, Jinbo | |
dc.contributor.author | Hall, Jessica Ann | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.date.accessioned | 2017-05-10T18:06:19Z | |
dc.date.available | 2017-05-10T18:06:19Z | |
dc.date.issued | 2014-08-01 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/24076 | |
dc.description.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. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This article is made available under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND 3.0) License. | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/ | en_US |
dc.title | Development of Radamide Analogs as Grp94 Inhibitors | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Muth, Aaron | |
kusw.kuauthor | Crowley, Vincent | |
kusw.kuauthor | Khandelwal, Anuj | |
kusw.kuauthor | Mishra, Sanket | |
kusw.kuauthor | Zhao, Jinbo | |
kusw.kuauthor | Hall, Jessica | |
kusw.kuauthor | Blagg, Brian S. J. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1016/j.bmc.2014.05.075 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-6817-7369
https://orcid.org/0000-0002-5261-7366 | |
dc.identifier.orcid | https://orcid.org/0000-0003-4492-4400 | |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC4142655 | en_US |
dc.rights.accessrights | openAccess | |