Design, synthesis and biological evaluation of plant-derived miliusol derivatives achieve TNBC profound regression in vivo.

Triple-negative breast cancer has become a major problem in clinical treatment due to its high heterogeneity, and Plant-derived drug discovery has been the focus of attention for novel anti-tumor therapeutics. In this study, Miliusol, a natural product isolated from the rarely reported plant Miliusa tenuistipitata, was identified as the lead compound, and 25 miliusol derivatives were designed and synthesized under antiproliferative activity guidance. The results revealed that ZMF-24 was demonstrated to have potent anti-TNBC proliferation with IC 50 values of 0.22 μM and 0.44 μM in BT-549 cells and MDA-MB-231 cells respectively with low cytotoxicity to MCF10A cells, and could significantly downregulate proliferation and migration markers. Through RNAseq analysis, molecular docking and CETSA experiment, we found that ZMF-24 could inhibit Eukaryotic translation initiation factor 3 subunit D (EIF3D) that further disrupted the energy supply of TNBC by inhibiting glycolysis, induced profound TNBC apoptosis by stimulating persistent ER stress. Importantly, ZMF-24 exhibited remarkable anti-proliferation and anti-metastasis potential in nude mice xenograft TNBC model without obvious toxicity. Collectively, the findings demonstrate ZMF-24 has significant potential as a potent chemotherapy agent against triple-negative breast cancer.