Discovery of hydrazide-based PI3K/HDAC dual inhibitors with enhanced pro-apoptotic activity in lymphoma cells

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC) are frequently overexpressed in various cancers.
• Concurrent inhibition of PI3K and HDAC pathways may offer synergistic anticancer effects by inhibiting tumor proliferation and inducing apoptosis.

Purpose of the Study:

• To rationally design and synthesize novel dual-target inhibitors of PI3K and HDAC.
• To evaluate the inhibitory activities and antiproliferative effects of the synthesized compounds.

Main Methods:

• Design and synthesis of novel compounds by integrating PI3K inhibitor ZSTK474 pharmacophore with HDAC inhibitor 11h moiety.
• In vitro evaluation of inhibitory activity against PI3K isoforms (α, β, γ, δ) and HDAC1-3.
• Assessment of antiproliferative activity against various tumor cell lines and apoptosis induction in mantle cell lymphoma Jeko-1 cells.

Main Results:

• Representative compound 31f demonstrated potent PI3K (IC50 = 2.5–80.5 nM) and HDAC1-3 (IC50 = 1.9–75.5 nM) inhibitory activities.
• Compound 31f exhibited significant antiproliferative effects across multiple tumor cell lines.
• In Jeko-1 cells, 31f showed superior efficacy in inducing apoptosis compared to single-target inhibitors.

Conclusions:

• The study successfully developed novel hydrazide-based dual PI3K/HDAC inhibitors.
• Compound 31f represents a promising lead candidate for further investigation in cancer therapy.
• These findings provide valuable insights for the development of next-generation dual-target anticancer agents.