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

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

Affiliations

  • 1 Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. Electronic address: jie.bao@helsinski.fi.
  • 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: jing.tang@helsinki.fi.
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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