Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor
| العنوان: | Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor |
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| المؤلفون: | Chitra Subramanian, Robert L. Matts, Brian S. J. Blagg, Anuj Khandelwal, Weiya Liu, Jeffery M. Holzbeierlein, Junpeng Deng, Mark S. Cohen, Victor W. Day, Sanket J. Mishra, Caitlin N. Kent, Maurie Balch, Shuxia Peng |
| المصدر: | Nature Communications, Vol 9, Iss 1, Pp 1-7 (2018) Nature Communications |
| بيانات النشر: | Nature Publishing Group, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Gene isoform, Science, Drug Evaluation, Preclinical, General Physics and Astronomy, Antineoplastic Agents, Article, General Biochemistry, Genetics and Molecular Biology, Structure-Activity Relationship, 03 medical and health sciences, Cell Line, Tumor, Heat shock protein, polycyclic compounds, medicine, Humans, Protein Isoforms, Structure–activity relationship, HSP90 Heat-Shock Proteins, Heat shock, lcsh:Science, Multidisciplinary, biology, Chemistry, HEK 293 cells, Cancer, Hydrogen Bonding, General Chemistry, medicine.disease, Hsp90, 3. Good health, Cell biology, HEK293 Cells, 030104 developmental biology, Drug Design, biology.protein, Protein folding, lcsh:Q |
| الوصف: | 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. The molecular chaperone Hsp90 oversees the folding of many proteins associated with cancer progression but existing small-molecule inhibitors of this pathway are not isoform-selective. Here, the authors rationally design an Hsp90 inhibitor that displays high selectivity for the Hsp90β isoform. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ca0d3fd460c06cb7b268c988c06edc1Test http://link.springer.com/article/10.1038/s41467-017-02013-1Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4ca0d3fd460c06cb7b268c988c06edc1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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