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

Jie Bao; Sanna Pikkusaari; Jun Dai; Samuel Leppiniemi; Wenjun Huang; Weiming Yang; Anu Anil; Mirva Pääkkönen; Chuqi Lei; Eva Daniela Mendoza-Ortiz; Ezgi Karagöz; Johanna Eriksson; Min Li; Johanna Hynninen; Otto Kauko; Anniina Färkkilä; Anna Vähärautio; Sampsa Hautaniemi; Liisa Kauppi; Jing Tang

doi:10.1016/j.biopha.2025.118716

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

Jie Bao^*
, Sanna Pikkusaari
, Jun Dai
, Samuel Leppiniemi
, Wenjun Huang
, Weiming Yang
, Anu Anil
, Mirva Pääkkönen
, Chuqi Lei
, Eva Daniela Mendoza-Ortiz
, Ezgi Karagöz
, Johanna Eriksson
, Min Li
, Johanna Hynninen
, Otto Kauko
, Anniina Färkkilä
, Anna Vähärautio
, Sampsa Hautaniemi
, Liisa Kauppi
, Jing Tang^*

^*Corresponding author for this work

Turku Bioscience Centre

Research output: Contribution to journal › Article › Scientific › peer-review

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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.

Original language	English
Article number	118716
Journal	Biomedicine and Pharmacotherapy
Volume	193
DOIs	https://doi.org/10.1016/j.biopha.2025.118716
Publication status	Published - Dec 2025
MoE publication type	A1 Journal article-refereed

Funding

Proteomics analyses were performed at the Turku Proteomics Facility, University of Turku and Åbo Akademi University. The facility is supported by Biocenter Finland. Proteomics analyses were performed at the Turku Proteomics Facility, University of Turku and Åbo Akademi University. The facility is supported by Biocenter Finland. FIMM High Content Imaging unit services were used for imaging analysis. Open access is funded by Helsinki University Library. JB and JT designed the project; JB conducted the project and wrote the manuscript; SP, AA and EK performed DNA damage experiment supervised by LK; JD performed flow cytometry experiments; JH provided the samples and clinical parameters for analyses.; SL performed clinical data analysis supervised by SH; WY performed pathway enrichment analyses; MP and OK (Turku Proteomic Core Facility) performed PISA experiment; DM performed drug response study together with JB; CL performed protein docking (SDR39U1 and BX/OSU/GSK) experiment supervised by ML; WH performed docking between BX-912 and HES1. JE, JH, AV, SH, LK and JT reviewed the manuscript. SH: European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 965193 (DECIDER), the Sigrid Jusélius Foundation and Cancer Foundation Finland .

Keywords

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

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10.1016/j.biopha.2025.118716Licence: CC BY

1-s2.0-S0753332225009102-mainFinal published version, 10.1 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe202601279141

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Bao, J., Pikkusaari, S., Dai, J., Leppiniemi, S., Huang, W., Yang, W., Anil, A., Pääkkönen, M., Lei, C., Mendoza-Ortiz, E. D., Karagöz, E., Eriksson, J., Li, M., Hynninen, J., Kauko, O., Färkkilä, A., Vähärautio, A., Hautaniemi, S., Kauppi, L., & Tang, J. (2025). Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma. Biomedicine and Pharmacotherapy, 193, Article 118716. https://doi.org/10.1016/j.biopha.2025.118716

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title = "Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma",

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{\textquoteright} power to reveal hidden drug activities, and propose sequential cell-cycle targeting to improve treatment efficacy.",

keywords = "Cell division, drug off-target, Ovarian high-grade serous cancer, Protein-protein interaction, Proteomics, Ovarian high-grade serous cancer, Proteomics, Protein-protein interaction, Cell division, drug off-target",

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year = "2025",

month = dec,

doi = "10.1016/j.biopha.2025.118716",

language = "English",

volume = "193",

journal = "Biomedicine and Pharmacotherapy",

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Bao, J, Pikkusaari, S, Dai, J, Leppiniemi, S, Huang, W, Yang, W, Anil, A, Pääkkönen, M, Lei, C, Mendoza-Ortiz, ED, Karagöz, E, Eriksson, J, Li, M, Hynninen, J, Kauko, O, Färkkilä, A, Vähärautio, A, Hautaniemi, S, Kauppi, L & Tang, J 2025, 'Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma', Biomedicine and Pharmacotherapy, vol. 193, 118716. https://doi.org/10.1016/j.biopha.2025.118716

TY - JOUR

T1 - Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma

AU - Bao, Jie

AU - Pikkusaari, Sanna

AU - Dai, Jun

AU - Leppiniemi, Samuel

AU - Huang, Wenjun

AU - Yang, Weiming

AU - Anil, Anu

AU - Pääkkönen, Mirva

AU - Lei, Chuqi

AU - Mendoza-Ortiz, Eva Daniela

AU - Karagöz, Ezgi

AU - Eriksson, Johanna

AU - Li, Min

AU - Hynninen, Johanna

AU - Kauko, Otto

AU - Färkkilä, Anniina

AU - Vähärautio, Anna

AU - Hautaniemi, Sampsa

AU - Kauppi, Liisa

AU - Tang, Jing

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - Cell division

KW - drug off-target

KW - Ovarian high-grade serous cancer

KW - Protein-protein interaction

KW - Proteomics

KW - Ovarian high-grade serous cancer

KW - Proteomics

KW - Protein-protein interaction

KW - Cell division

KW - drug off-target

UR - https://www.scopus.com/pages/publications/105021093136

U2 - 10.1016/j.biopha.2025.118716

DO - 10.1016/j.biopha.2025.118716

M3 - Article

C2 - 41202420

AN - SCOPUS:105021093136

SN - 0753-3322

VL - 193

JO - Biomedicine and Pharmacotherapy

JF - Biomedicine and Pharmacotherapy

M1 - 118716

ER -

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

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