Structure-Based Discovery of Hsp90/HDAC6 Dual Inhibitors Targeting Aggressive Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• HDAC6 and Hsp90 are crucial in the androgen response pathway, vital in prostate cancer (PC) progression.
• Their interplay suggests combined inhibition as a therapeutic strategy for aggressive PC.
• Targeting these proteins offers a novel approach to combatting treatment-resistant PC.

Purpose of the Study:

• To design and discover dual inhibitors targeting both HDAC6 and Hsp90.
• To identify a potent and selective compound with favorable drug-like properties for PC treatment.
• To evaluate the efficacy of dual inhibition in preclinical models of prostate cancer.

Main Methods:

• Structure-based drug design utilizing crystal structures of HDAC6 and Hsp90.
• Synthesis and characterization of novel dual inhibitors.
• In vitro antiproliferative assays in PC cell lines.
• In vivo evaluation using 3D tumor spheroid models.
• Combination studies to assess synergistic effects.

Main Results:

• Discovery of compound 17, a potent, balanced, and selective dual inhibitor of HDAC6 and Hsp90.
• Compound 17 exhibited significant antiproliferative activity across various PC cell lines.
• Demonstrated marked anticancer effects in 3D tumor spheroids, targeting both established and initiating cells.
• Combination studies revealed significant synergistic effects, surpassing single-target inhibitor co-administration.

Conclusions:

• Compound 17 represents a promising dual inhibitor for aggressive prostate cancer.
• Its ability to target key regulators and exhibit synergistic effects warrants further preclinical investigation.
• This dual-targeting strategy holds potential for overcoming resistance mechanisms in advanced PC.