Hsp90β-Selective Inhibitors: Probing the Solvent-Accessible Frontier

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Heat shock protein 90 (Hsp90) inhibitors are investigated for cancer and neurological disorders.
• Pan-inhibition of Hsp90 isoforms (Hsp90α and Hsp90β) leads to toxicity, hindering clinical applications.
• Isoform-selective Hsp90 inhibitors are needed to improve therapeutic efficacy and reduce side effects.

Purpose of the Study:

• To synthesize and evaluate novel Hsp90β-selective inhibitors.
• To elucidate structure-activity relationships (SAR) for Hsp90β inhibitors.
• To assess the in vitro and in cellulo efficacy of newly developed analogs.

Main Methods:

• Synthesis of nineteen additional Hsp90β inhibitor analogs.
• Evaluation of binding affinity and selectivity for cytosolic Hsp90 isoforms.
• Structure-activity relationship analysis focusing on the solvent-exposed region.

Main Results:

• Identified structural modifications that tolerate steric bulk and require specific heteroatoms for high Hsp90β affinity and selectivity.
• Demonstrated selective inhibition of Hsp90β in cellulo with the synthesized compounds.
• Established further SAR for Hsp90β-selective inhibitors.

Conclusions:

• Subtle modifications in the solvent-exposed region significantly impact Hsp90 inhibitor affinity and selectivity.
• The developed compounds show potential for selective Hsp90β inhibition.
• This work supports the continued development of Hsp90 isoform-selective inhibitors for therapeutic use.