AUTHOR=Wurnig Silas , Vogt Melina , Hogenkamp Julian , Dienstbier Niklas , Borkhardt Arndt , Bhatia Sanil , Hansen Finn K. TITLE=Development of the first geldanamycin-based HSP90 degraders JOURNAL=Frontiers in Chemistry VOLUME=11 YEAR=2023 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1219883 DOI=10.3389/fchem.2023.1219883 ISSN=2296-2646 ABSTRACT=

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 HSP90α and HSP90β levels in cells utilizing the ubiquitin–proteasome pathway.