Development of the first geldanamycin-based HSP90 degraders

Despite the early clinical promise, adverse events such as acquired resistance and dose-limiting toxicities have barred the widespread use of HSP90 inhibitors as anticancer drugs. A new approach involving proteolysis-targeting chimeras (PROTACs) to degrade the protein instead of inhibiting it may overcome these problems. In this work, we describe the design, synthesis, and evaluation of cereblon-recruiting geldanamycin-based HSP90 degraders based on the PROTAC technology. Our best degrader, 3a, effectively decreased HSP90 alpha and HSP90 beta levels in cells utilizing the ubiquitin-proteasome pathway.

Automated summary

Despite limitations with HSP90 inhibitors as anticancer drugs, a new approach using PROTACs to degrade the protein shows promise. This study focuses on designing and evaluating geldanamycin-based HSP90 degraders based on the PROTAC technology. The best degrader, 3a, effectively reduced HSP90 alpha and HSP90 beta levels in cells using the ubiquitin-proteasome pathway.