期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02013-1
关键词
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资金
- National Institutes of Health [CA120458, AI113539]
- National Institutes of Health Graduate Training Program in Dynamic Aspects of Chemical Biology Grant [T32 GM08545]
- OAES [OKL02959, AI133589]
- NIH [S10OD016360, S10RR024664]
- NSF [0320648, CHE-0923449]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1625923] Funding Source: National Science Foundation
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 Hsp90 beta, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90 beta-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.
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