The 90 kDa heat shock protein (Hsp90) is a member of the molecular chaperone family that processes newly synthesized polypeptides into their three-dimensional biologically active form. Additionally, Hsp90 assists in the stabilizing, trafficking and refolding of denatured proteins as well regulating the triage of numerous client proteins by participating in ubiquitin-proteasome pathway. Many Hsp90-client proteins are critical for the pathogenesis of cancer, neurodegeneration and/or viral infection. As a result, Hsp90 became a sought-after chemotherapeutic target, and that leads to entry of seventeen small-molecule Hsp90 inhibitors into clinical trials for cancers, all of which bind N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be associated with various toxicities (hepatotoxicity, cardiotoxicity, renal toxicity, and/or ocular toxicity) as well induction of  pro-survival heat shock response. Development of isoform selective inhibitors is an alternative approach to circumvent or limit some of the detriments.<br/>           <br/>            The cytosolic Hsp90 isoforms (Hsp90α and Hsp90β) modulate the activity of numerous Hsp90 client proteins that regulate cancer progression. Since the N-terminal ATP-binding site is highly conserved, designing inhibitors that selectively target one cytosolic Hsp90 isoform over the other became challenging. In our current work, a structure-based approach has been employed to develop Hsp90β-selective inhibitors, which exhibit both high selectivity and affinity. The efficacy of these inhibitors has been evaluated against an array of cancers, revealing an Hsp90 isoform-dependent profile.<br/>

Structure-guided approach toward the design, synthesis and biological evaluation of Hsp90β N-terminal isoform-selective inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.