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Publication Abstract from PubMed

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 Hsp90beta, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90beta-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.

Structure-guided design of an Hsp90beta N-terminal isoform-selective inhibitor.,Khandelwal A, Kent CN, Balch M, Peng S, Mishra SJ, Deng J, Day VW, Liu W, Subramanian C, Cohen M, Holzbeierlein JM, Matts R, Blagg BSJ Nat Commun. 2018 Jan 30;9(1):425. doi: 10.1038/s41467-017-02013-1. PMID:29382832^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.