Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• HDAC6 and Hsp90 form a complex crucial for protein homeostasis.
• Their interplay is significant in cancer, making them promising therapeutic targets.
• Developing dual inhibitors for HDAC6 and Hsp90 is a key research area.

Purpose of the Study:

• To design, synthesize, and evaluate bifunctional inhibitors targeting the HDAC6-Hsp90 complex.
• To identify a potent molecule with dual inhibitory activity against HDAC6 and Hsp90.
• To assess the therapeutic potential of such dual inhibitors in cancer treatment.

Main Methods:

• Chemical synthesis of bifunctional inhibitor compounds.
• In vitro biological evaluation of inhibitory activity against HDAC6 and Hsp90.
• Assessment of antiproliferative effects on cancer cell lines, including drug-resistant models.
• In vivo efficacy studies using a non-small cell lung cancer xenograft model.

Main Results:

• Compound 6e demonstrated significant dual inhibitory activity against HDAC6 (IC50=106 nM) and Hsp90 (IC50=61 nM).
• Compound 6e induced substrate acetylation (α-tubulin) and client degradation (Her2, EGFR, Akt, HDAC6).
• Potent antiproliferative effects (GI50=1.7 μM) were observed in gefitinib-resistant NSCLC cells, with significant tumor growth inhibition in vivo without apparent toxicity.

Conclusions:

• Compound 6e is a potent dual inhibitor of HDAC6 and Hsp90.
• It exhibits promising anticancer activity in preclinical models of non-small cell lung cancer.
• Compound 6e serves as a valuable lead for developing novel cancer therapeutics targeting both HDAC6 and Hsp90.