Rationally modified SNX-class Hsp90 inhibitors disrupt extracellular fibronectin assembly without intracellular Hsp90...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Heat shock protein 90 (Hsp90) is a promising cancer therapeutic target, but its inhibition often triggers a compensatory heat shock response (HSR).
• Extracellular Hsp90 (eHsp90) plays a role in tumor microenvironment, promoting cell invasiveness and metastasis through interactions with clients like fibronectin.

Purpose of the Study:

• To develop novel Hsp90 inhibitors that selectively target extracellular Hsp90 (eHsp90) without inducing the intracellular heat shock response (HSR).
• To investigate the potential of these new compounds in disrupting extracellular matrix components crucial for tumor metastasis.

Main Methods:

• Rational modification of existing Hsp90 inhibitors (SNX2112 and SNX25a) to create new chemical entities.
• Assay development to assess Hsp90 inhibitory activity, HSR induction, and disruption of extracellular fibronectin network assembly.
• Evaluation of compounds at non-cytotoxic concentrations.

Main Results:

• Four novel Hsp90 inhibitory compounds were synthesized, designed to limit interaction with intracellular Hsp90 and avoid HSR stimulation.
• Two compounds, designated 10 and 11, effectively disrupted the extracellular fibronectin network at non-cytotoxic concentrations.
• These compounds demonstrated selective activity against extracellular targets without inducing the compensatory HSR.

Conclusions:

• Modified Hsp90 inhibitors can selectively target eHsp90 and its pro-oncogenic functions.
• Compounds 10 and 11 are valuable tool compounds for further research into targeting eHsp90 to inhibit tumor invasiveness and metastasis.
• This approach offers a promising strategy to overcome limitations of previous Hsp90-targeted cancer therapies.