Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2 Journal Article
| Authors: | Patel, P. D.; Yan, P.; Seidler, P. M.; Patel, H. J.; Sun, W.; Yang, C.; Que, N. S.; Taldone, T.; Finotti, P.; Stephani, R. A.; Gewirth, D. T.; Chiosis, G. |
| Article Title: | Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2 |
| Abstract: | Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers. © 2013 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; human cell; breast cancer; epidermal growth factor receptor 2; drug structure; drug screening; drug selectivity; drug specificity; cancer cell; heat shock protein 90 inhibitor; gene insertion; purine; competitive inhibition; glucose regulated protein 94; combinatorial library |
| Journal Title: | Nature Chemical Biology |
| Volume: | 9 |
| Issue: | 11 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2013-01-01 |
| Start Page: | 677 |
| End Page: | 684 |
| Language: | English |
| DOI: | 10.1038/nchembio.1335 |
| PROVIDER: | scopus |
| PUBMED: | 23995768 |
| PMCID: | PMC3982621 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):1 - "Export Date: 2 December 2013" - "CODEN: NCBAB" - "Source: Scopus" |
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