Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Prostate cancer treatment often involves androgen receptor antagonists.
• Histone deacetylase inhibitors (HDACi) can enhance antiandrogen efficacy.
• Combining these agents may offer improved therapeutic outcomes.

Purpose of the Study:

• To design, synthesize, and evaluate novel antiandrogen/HDACi hybrid molecules.
• To assess the bifunctionality and antiproliferative activity of these hybrids.
• To determine the therapeutic potential of these novel hybrid compounds.

Main Methods:

• Synthesis of hybrid molecules integrating enzalutamide with SAHA or entinostat structural motifs.
• Fluorometric histone deacetylase (HDAC) assay to confirm HDAC inhibition.
• Bioluminescence resonance energy transfer (BRET) assay to assess antiandrogen activity.
• Antiproliferative assays on prostate cancer cell lines.

Main Results:

• Synthesized hybrids retained dual antiandrogen and HDAC inhibitory functions.
• Hybrids with o-aminoanilide-based HDACi motifs showed superior antiproliferative effects compared to hydroxamic acid-based HDACi hybrids.
• The novel compounds demonstrated selectivity for epithelial cancer cells over stromal cells.

Conclusions:

• Novel antiandrogen/HDACi hybrids possess bifunctional activity.
• Specific hybrid designs exhibit enhanced efficacy and selectivity in prostate cancer models.
• These findings suggest a potential therapeutic window for these hybrid compounds in prostate cancer therapy.