Development of the first geldanamycin-based HSP90 degraders

Silas Wurnig; Melina Vogt; Julian Hogenkamp; Niklas Dienstbier; Arndt Borkhardt; Sanil Bhatia; Finn K Hansen

doi:10.3389/fchem.2023.1219883

Development of the first geldanamycin-based HSP90 degraders

Front Chem. 2023 Jun 28:11:1219883. doi: 10.3389/fchem.2023.1219883. eCollection 2023.

Authors

Silas Wurnig¹, Melina Vogt², Julian Hogenkamp², Niklas Dienstbier², Arndt Borkhardt², Sanil Bhatia², Finn K Hansen¹

Affiliations

¹ Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
² Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

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.

Keywords: Hsp90; PROTAC; cancer; cereblon; heat shock protein.

Grants and funding

This work was supported by the Open Access Publication Fund of the University of Bonn. This work was funded in part by the Düsseldorf School of Oncology (DSO-‘Netzwerkverbundes) and Forschungskommission (2021-19) HHU Düsseldorf to SB.