Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma
Biomed Pharmacother. 2025 Nov 6;193:118716. doi: 10.1016/j.biopha.2025.118716. Online ahead of print.
Published on November 7, 2025
ABSTRACT
Ovarian high-grade serous cancer (HGSC) is the most aggressive ovarian cancer subtype with limited treatment options. We identify the PDPK1 inhibitor BX-912 as a promising candidate, showing strong single-agent activity and synergy with the PARP inhibitor olaparib, independent of BRCA status. Unexpectedly, BX-912 induces multinucleation, a phenotype not seen with other PDPK1 inhibitors. Proteome Integral Solubility Alteration (PISA) assay reveals HES1 as a functional off-target, while structural modeling suggested BX-912 acts as a protein-protein interaction modulator, driving nuclear accumulation of HES1 complexes and hence inducing mitotic catastrophe. Cell-cycle analyses confirm enhanced DNA damage response and G2/M arrest when combined with olaparib. These findings uncover a novel mechanism for BX-912, establish HES1 inhibition as a therapeutic strategy in HGSC, demonstrate proteomics’ power to reveal hidden drug activities, and propose sequential cell-cycle targeting to improve treatment efficacy.
PMID:41202420 | DOI:10.1016/j.biopha.2025.118716