Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor

Anuj Khandelwal, Caitlin N. Kent, Maurie Balch, Shuxia Peng, Sanket J. Mishra, Junpeng Deng, Victor W. Day, Weiya Liu, Chitra Subramanian, Mark Cohen, Jeffery M. Holzbeierlein, Robert Matts and Brian S. J. Blagg ()
Additional contact information
Anuj Khandelwal: The University of Kansas
Caitlin N. Kent: The University of Notre Dame
Maurie Balch: Oklahoma State University
Shuxia Peng: Oklahoma State University
Sanket J. Mishra: The University of Kansas
Junpeng Deng: Oklahoma State University
Victor W. Day: The University of Kansas
Weiya Liu: University of Kansas Medical Center
Chitra Subramanian: University of Michigan School of Medicine
Mark Cohen: University of Michigan School of Medicine
Jeffery M. Holzbeierlein: University of Kansas Medical Center
Robert Matts: Oklahoma State University
Brian S. J. Blagg: The University of Notre Dame

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02013-1

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