Chimeric Hsp90β-Selective Inhibitors Confer Enhanced Affinity, Selectivity, and Drug-Like Properties

Abstract The clinical evaluation of 90 kD heat shock protein (Hsp90) inhibitors has been hindered by their detrimental, pan-inhibitory activities. Consequently, the development of Hsp90 isoform-selective inhibitors has been pursued. Although prior compounds have elucidated the roles of Hsp90β in cancer immunotherapy and opioid therapy, their sub-optimal drug-like properties have required extensive optimization campaigns to enhance this scaffold’s pharmacological profile. The work presented herein expands upon previous efforts by introducing simultaneous modifications to the “northern” indazolone fragment and “southwestern” appendage to determine whether combinations of the properties at these regions can produce improved Hsp90β-selective inhibitors. These chimeric inhibitors reveal that such modifications can retain Hsp90β affinity/selectivity, while modulating key pharmacokinetic parameters and anticancer activity. Notably, one derivative (8b) also exhibits oral bioavailability and enhances opioid antinociception in a murine model for chronic pain. These findings support the continued development of Hsp90β-selective inhibitors for anticancer therapy, chronic pain management, and other disease indications.