A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma
Tekijät: Bao, Jie; Pikkusaari, Sanna; Dai, Jun; Leppiniemi, Samuel; Huang, Wenjun; Yang, Weiming; Anil, Anu; Pääkkönen, Mirva; Lei, Chuqi; Mendoza-Ortiz, Eva Daniela; Karagöz, Ezgi; Eriksson, Johanna; Li, Min; Hynninen, Johanna; Kauko, Otto; Färkkilä, Anniina; Vähärautio, Anna; Hautaniemi, Sampsa; Kauppi, Liisa; Tang, Jing
Kustantaja: Elsevier
Julkaisuvuosi: 2025
Lehti: Biomedicine and Pharmacotherapy
Artikkelin numero: 118716
Vuosikerta: 193
ISSN: 0753-3322
eISSN: 1950-6007
DOI: https://doi.org/10.1016/j.biopha.2025.118716
Julkaisun avoimuus kirjaamishetkellä: Avoimesti saatavilla
Julkaisukanavan avoimuus : Kokonaan avoin julkaisukanava
Verkko-osoite: https://doi.org/10.1016/j.biopha.2025.118716
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/505281223
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
Julkaisussa olevat rahoitustiedot:
SL: The iCANDOC Precision Cancer Medicine pilot
SH: European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 965193 (DECIDER), the Sigrid Jusélius Foundation and Cancer Foundation Finland.
LK: the Sigrid Jusélius Foundation and Cancer Foundation Finland
WY: The EDUFI Fellowship from the Finnish National Agency for Education
JB and JT: European Research Council (DrugComb No. 716063), The Sigrid Jusélius Foundation, The Academy of Finland (No. 317680, 320131, 359752)
