Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 19, Pages 10547-10551Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202015422
Keywords
drug discovery; Hsp90 alpha; isoform selectivity; structure-based drug design
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Funding
- National Institutes of Health [CA213566, CA219907]
- Oklahoma Agricultural Experiment Station [OKL03159, OKL03060]
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20GM103640]
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The study focuses on a new class of anti-cancer agents targeting Hsp90 protein - Hsp90 alpha-selective inhibitors, which demonstrate specificity and broad selectivity, showing promise for significant impact in cancer treatment.
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression of cancer, and consequently, inhibition of the Hsp90 protein folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with Hsp90 N-terminal inhibitors have encountered deleterious side effects and toxicities, which appear to result from the pan-inhibition of all four Hsp90 isoforms. Therefore, the development of isoform-selective Hsp90 inhibitors is sought to delineate the pathological role played by each isoform. Herein, we describe a structure-based approach that was used to design the first Hsp90 alpha-selective inhibitors, which exhibit >50-fold selectivity versus other Hsp90 isoforms.
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