Hsp90β-Selective Inhibitors: Probing the Solvent-Accessible Frontier

Inhibitors of the 90- kDa heat shock protein (Hsp90) family, especially Hsp90β, have been a sought-after therapeutic strategy for the treatment of cancer, neurological disorders, and other diseases. Furthermore, recent studies suggest that their coadministration with other therapies can enhance efficacy. pan-Inhibition of the cytosolic Hsp90α and Hsp90β isoforms has proven to be problematic, since the on-target toxicities have resulted in the failure of most Hsp90 inhibitors that entered clinical trials. Consequently, such outcomes highlight the demand for isoform-selective inhibitors that overcome these detriments. Previously, we reported that subtle modifications to the solvent-exposed region of Hsp90β-selective inhibitors can significantly impact affinity and selectivity. Consequently, nineteen additional analogs were synthesized and evaluated for their ability to bind the cytosolic Hsp90 isoforms, as well as elucidate further structure-activity relationships (SAR) at this region of the molecule. The work herein reveals the extent to which appendages with steric bulk are tolerated, as well as the importance of heteroatoms to maintain high Hsp90β affinity and selectivity. Biological evaluation of these compounds supports the selective inhibition of Hsp90β in cellulo, which is encouraging for the continued exploration of Hsp90 isoform-selective inhibitors for therapeutic applications.