Structure-guided design of an Hsp90â N-terminal isoform-selective inhibitor
dc.contributor.author | Khandelwal, Anuj | |
dc.contributor.author | Kent, Caitlin N. | |
dc.contributor.author | Balch, Maurie | |
dc.contributor.author | Peng, Shuxia | |
dc.contributor.author | Mishra, Sanket J. | |
dc.contributor.author | Deng, Junpeng | |
dc.contributor.author | Day, Victor W. | |
dc.contributor.author | Liu, Weiya | |
dc.contributor.author | Subramanian, Chitra | |
dc.contributor.author | Cohen, Mark S. | |
dc.contributor.author | Holzbeierlein, Jeffery M. | |
dc.contributor.author | Matts, Robert L. | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.date.accessioned | 2018-02-08T18:48:43Z | |
dc.date.available | 2018-02-08T18:48:43Z | |
dc.date.issued | 2018-01-30 | |
dc.identifier.citation | Khandelwal, A., Kent, C. N., Balch, M., Peng, S., Mishra, S. J., Deng, J., ... & Holzbeierlein, J. M. (2018). Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor. Nature communications, 9(1), 425. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/25939 | |
dc.description.abstract | The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method to overcome the detriments associated with pan-inhibition. | en_US |
dc.publisher | Nature Publishing Group | en_US |
dc.rights | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.title | Structure-guided design of an Hsp90â N-terminal isoform-selective inhibitor | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Khandelwal, Anuj | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1038/s41467-017-02013-1 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-4492-4400 | |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC5789826 | en_US |
dc.rights.accessrights | openAccess | en_US |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's license is described as: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.