Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma

  • Biomed Pharmacother. 2025 Dec:193:118716. doi: 10.1016/j.biopha.2025.118716.
Jie Bao  1 ,  Sanna Pikkusaari  2 ,  Jun Dai  2 ,  Samuel Leppiniemi  2 ,  Wenjun Huang  3 ,  Weiming Yang  2 ,  Anu Anil  2 ,  Mirva Pääkkönen  4 ,  Chuqi Lei  5 ,  Eva Daniela Mendoza-Ortiz  6 ,  Ezgi Karagöz  2 ,  Johanna Eriksson  2 ,  Min Li  5 ,  Johanna Hynninen  7 ,  Otto Kauko  4 ,  Anniina Färkkilä  8 ,  Anna Vähärautio  9 ,  Sampsa Hautaniemi  2 ,  Liisa Kauppi  2 ,  Jing Tang  10
Affiliations
  • 1. Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. Electronic address: [email protected].
  • 2. Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.
  • 3. Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Faculty of Pharmacy, University of Helsinki, Finland.
  • 4. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
  • 5. School of Computer Science and Engineering, Central South University, Changsha, China.
  • 6. Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; iCAN Digital Precision Medicine Flagship, University of Helsinki, Helsinki, Finland.
  • 7. Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland.
  • 8. Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; iCAN Digital Precision Medicine Flagship, University of Helsinki, Helsinki, Finland.
  • 9. Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Foundation for the Finnish Cancer Institute, Helsinki, Finland.
  • 10. Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Helsinki Institute of Sustainability Science, HELSUS, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: [email protected].
PMID: 41202420 DOI: 10.1016/j.biopha.2025.118716
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.

Keywords
Cell division; Ovarian high-grade serous cancer; Protein-protein interaction; Proteomics; drug off-target.
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