Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma
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.
Authors
- Jie Bao (ORCID: https://orcid.org/0000-0002-1993-7309)
- Wenjun Huang (ORCID: https://orcid.org/0000-0001-8887-309X)
- Sampsa Hautaniemi (ORCID: https://orcid.org/0000-0002-7749-2694)
- Johanna Hynninen (ORCID: https://orcid.org/0000-0002-0854-7225)
- Ezgi Karagöz (ORCID: https://orcid.org/0000-0001-6522-0088)
- Mirva Pääkkönen (ORCID: https://orcid.org/0000-0002-3184-3938)
- Jun Dai (ORCID: https://orcid.org/0000-0001-6643-5216)
- Liisa Kauppi (ORCID: https://orcid.org/0000-0002-6759-8997)
- Otto Kauko (ORCID: https://orcid.org/0000-0001-8948-9452)
- Sanna Pikkusaari (ORCID: https://orcid.org/0000-0002-2966-0446)
- Anna Vähärautio (ORCID: https://orcid.org/0000-0003-4721-3954)
- Anniina Färkkilä (ORCID: https://orcid.org/0000-0002-3558-6617)
- Jing Tang (ORCID: https://orcid.org/0000-0001-7480-7710)
- Chuqi Lei (ORCID: https://orcid.org/0009-0007-5234-9924)
- Min Li (ORCID: https://orcid.org/0000-0002-4662-4623)
- Johanna Eriksson (ORCID: https://orcid.org/0009-0006-2238-3227)
- Weiming Yang
- Samuel Leppiniemi (ORCID: https://orcid.org/0009-0006-3684-0206)
- Eva Daniela Mendoza-Ortiz (ORCID: https://orcid.org/0009-0000-2392-3316)
- Anu Anil (ORCID: https://orcid.org/0009-0008-4293-7893)
Institutions
- Åbo Akademi University (FI)
- University of Helsinki (FI)
- Central South University (CN)
- University of Turku (FI)
- Turku Centre for Computer Science (FI)
- Helsinki Institute of Physics (FI)
- Turku University Hospital (FI)
- Finnish Cancer Registry (FI)
- Helsinki Art Museum (FI)
- Finland University (FI)
- Institute for Molecular Medicine Finland (FI)
- Cancer Society of Finland (FI)
Publication Details
- Journal
- Biomedicine & Pharmacotherapy
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1016/j.biopha.2025.118716
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00