Development of the first geldanamycin-based HSP90 degraders

Frontiers in Chemistry

Chemistry

Arndt Borkhardt¹  Melina Vogt¹  Sanil Bhatia¹  Niklas Dienstbier¹  Julian Hogenkamp¹  Silas Wurnig²  Finn K. Hansen² 

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

关键词: cancer;    cereblon;    heat shock protein;    Hsp90;    PROTAC;   

DOI  :  10.3389/fchem.2023.1219883

 received in 2023-05-09, accepted in 2023-06-09,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Wurnig, Vogt, Hogenkamp, Dienstbier, Borkhardt, Bhatia and Hansen.

【 图 表 】

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