The evolution of heat shock protein 90 C-terminal inhibitors: From novobiocin to potential clinical candidates
Abstract
Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that regulates the maturation of various client proteins. Most therapeutic studies have focused on N-terminal Hsp90 inhibitors, but these are limited by dose-escalating toxicities that are caused by induction of the heat shock response. Leonard Neckers' discovery of novobiocin as a Hsp90 C-terminal inhibitor revealed an alternative mode to Hsp90 inhibition and established the C-terminal domain (CTD) as a therapeutic target. This review highlights recent advances in Hsp90 CTD inhibition and summarizes the evolution of novobiocin-based C-terminal inhibitors. Structure-activity relationship studies are discussed, demonstrating how medicinal chemistry optimization has produced CTD modulators with selective anti-proliferative or neuroprotective activities.
Fields of Study & Subjects
Heat shock proteins research
Peptidase Inhibition and Analysis
S100 Proteins and Annexins
Publication details
- Journal / source
- Cell Stress and Chaperones
- Publisher
- Elsevier BV
- Volume
- 31
- Issue
- 3
- Pages
- 100165–100165
- Publication date
- 7 March 2026
- Language
- EN