Development of Hsp90 C-Terminal Modulators: To Treat Two Diseases with One Target

The modulation of the heat shock protein 90 (Hsp90) C-terminal domain has emerged as a promising area of investigation due to its critical role in the chaperone cycle and protein homeostasis. Hsp90 is a ubiquitous molecular chaperone involved in the folding, stabilization, and activation of a wide array of client proteins, many of which are key regulators of cellular signaling pathways. Traditional approaches to targeting Hsp90 have focused on its N-terminal ATP-binding domain, but these strategies have often been limited by dose-limiting toxicity caused by induction of the heat shock response (HSR). Recent research has shifted toward the C-terminal domain of Hsp90, which presents a unique set of regulatory features and potential therapeutic advantages. Targeting the C-terminal domain can effectively disrupt the chaperone cycle, leading to selective degradation of oncogenic client proteins without induction of the HSR typically associated with N-terminal inhibitors.
This dissertation explores the structure activity relationship (SAR) on the Hsp90 C-terminal modulators, investigating the size and nature of Hsp90 C-terminal domain. Analysis of SAR via cell viability assays have led to the identification of some key features associated with C-terminal domain modulation. Moreover, we have developed small molecules that target the Hsp90 C-terminal domain, demonstrating potential as therapeutic agents in cancer and/or neurodegenerative diseases. These compounds exhibit a distinct mechanism of action, providing a new avenue for therapeutic intervention with potentially reduced side effects compared to conventional Hsp90 inhibitors. In summary, this work enhances our insights into the Hsp90 C-terminal domain's binding mechanisms and highlights its potential as a target for novel therapeutic strategies.