jm0c01700_si_001.pdf (1.37 MB)
The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with pan-Hsp90 Inhibition
journal contributionposted on 2021-01-11, 18:15 authored by Sanket J. Mishra, Weiya Liu, Kristin Beebe, Monimoy Banerjee, Caitlin N. Kent, Vitumbiko Munthali, John Koren, John A Taylor, Leonard M. Neckers, Jeffrey Holzbeierlein, Brian S. J. Blagg
The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which 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 for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms, which may lead to adverse effects. The development of Hsp90 isoform-selective inhibitors represents an alternative approach toward the treatment of cancer and may limit some of these detriments. Described herein, is a structure-based approach to develop 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 for overcoming the detriments associated with pan-inhibition.
Hsp 90 isoforms90 kD heat shock proteinsexhibit panHsp 90β-selective inhibitorsstudies supportcancer progressionHsp 90 proteinHsp 90 InhibitionHsp 90 N-terminusHsp 90 isoform-selective inhibitorsstructure-based approachalternative approachHsp 90 levelsOvercome Detriments AssociatedHsp 90machinery resultsHsp 90 clientsHsp 90β-Selective Inhibitorsoncogenic pathwayssmall-molecule inhibitorscombinatorial attackisoform-selective inhibitors