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.
Highlights
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression
Hsp90β is constitutively expressed in the cytoplasm, Hsp90α is expressed in the cytosol in response to cellular stress, Grp[94] resides in the endoplasmic reticulum, and Trap-1 is localized to the mitochondria[1,2,3]
These molecular chaperones are responsible for the conformational maturation, activation, and/or trafficking of ~300 Hsp90-dependent substrates[4,5,6,7,8,9]
Summary
Sequence alignment of the N-terminal ATP-binding domain of Hsp90α and Hsp90β reveals that Hsp90β contains Ala[52] and Leu[91] residues in lieu of Ser[52] and Ile[91], which are present in Hsp90α (Supplementary Fig. 1). There is a water-mediated network of hydrogen bonds that align at the bottom of the pocket surrounding the resorcinol ring of radicicol bound to each Hsp[90] isoform (Fig. 1c, d, and Supplementary Fig. 2). Similar to other Hsp[90] inhibitors, radicicol (Fig. 1b) exhibits pan-inhibitory activity. Thr[184] and Asp[93] (numbered for Hsp90β) produce hydrogen bonds with the carbonyl and 4-phenol of radicicol through three conserved water molecules. Overlay of the Hsp90α and Hsp90β co-crystal structures suggest these water molecules play different roles in each isoform as a consequence of the replacement of Ser[52] with Ala[52] in Hsp90β31. Modification to the 4-position of the resorcinol ring was sought to a
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