Work

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

Year: 2025

Type: article

Abstract: 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 (IC 50 = 2.5–80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC 50 = 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.

Source: European Journal of Medicinal Chemistry

DOI: 10.1016/j.ejmech.2025.117658

Authors: Baogeng Hou, Geng Jia, Zhongqiang Li, Yuqi Jiang, Yuxin Chen, Xiaoyang Li

Institutions: Ocean University of China, Marine Biomedical Research Institute of Qingdao

Language: English

Topic: Histone Deacetylase Inhibitors Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,650