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

PI3K and HDAC are concurrently upregulated in a variety of cancers, and simultaneous inhibition of PI3K and HDAC may synergistically inhibit tumor proliferation and induce apoptosis, providing a rationale for the study of dual-target PI3K/HDAC inhibitors. In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor 11h. Representative compound 31f possessed both PI3K (IC₅₀ = 2.5-80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC₅₀ = 1.9-75.5 nM for HDAC1-3). 31f showed potent antiproliferative activity against a variety of tumor cell lines. Meanwhile, we designed and synthesized tool molecule 39a, a HDAC inhibitor structurally similar to 31f. In the mantle cell lymphoma Jeko-1 cell line, 31f showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors.