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

Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitorThe 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.

Nat Commun. 2018 Jan 30;9(1):425.
doi: 10.1038/s41467-017-02013-1.


© 2018 Macmillan Publishers Limited.

  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.

Another SBC Highlight:

DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants

DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants



Structure. 2018 Jan 2;26(1):85-95.e3.
doi: 10.1016/j.str.2017.11.022.
Epub 2017 Dec 21.

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APS PDB Depositions from BioSync
SBC Sector 19 2016 2017 2018 TOTAL
PDB Depositions 232 29 185 35 03 04 5220

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