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IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy
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  • Published: 27 March 2026

IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy

  • Evangelia Goulielmaki1 na1,
  • Anna Tsapara1 na1,
  • Lydia Xenou1,
  • Zoe Johnson2,
  • Karolina Niewola-Staszkowska2,
  • Maria Tzardi3,
  • Eelco de Bree  ORCID: orcid.org/0000-0001-8422-37274 &
  • …
  • Evangelia A. Papakonstanti  ORCID: orcid.org/0000-0002-7119-60261 

Cell Death Discovery , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Breast cancer
  • Drug development

Abstract

The clinical approval of p110δ PI3K inhibitors raised hopes in treating aggressive tumours expressing high levels of non-mutated p110δ, however, the severe adverse effects that those inhibitors caused became a barrier to their clinical application. IOA-244 is the first-in-class, highly selective and non-ATP competitive p110δ PI3K inhibitor showing high selectivity and low toxicity in several preclinical models. Here we show that IOA-244, as a single agent treatment, blocks the progression of early phase breast tumours by attacking the survival of cancer cells and the polarisation of TAMs to a pro-tumourigenic phenotype leading to suppression of TAMs-expressed ATX. In established tumours, IOA-244 alone was insufficient to control the high levels of both M2-like macrophages and ATX, and while it reduced tumour progression, it did not completely block it. Full tumour control, however, was achieved when IOA-244 used in a combinatorial regimen with the PF-8380 ATX inhibitor. In agreement with the mouse model, the amount of CD163+/CD204+macrophages and ATX were much higher in grade III human breast carcinomas compared to grade I. Our work provides the first in vivo preclinical evidence showing that IOA-244 is a potential highly effective drug for breast cancer treatment and depending on the phase of the tumour can be used either as a single agent or as a combinatorial regimen.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper and/or are available upon request from the corresponding author. Full and uncropped western blots are shown in Supplementary Fig. 4.

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Acknowledgements

We are grateful to Giusy Di Conza (iOnctura) and Laurence Neff (iOnctura) for the critical reading of the manuscript. We are also truly grateful to Stavros Topouzis (Pharmacology Department, University of Patras) for manuscript editing. This research was supported by iOnctura (Project Number: 10179) and by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 3405).

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Author notes

  1. These authors contributed equally: Evangelia Goulielmaki, Anna Tsapara.

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece

    Evangelia Goulielmaki, Anna Tsapara, Lydia Xenou & Evangelia A. Papakonstanti

  2. iOnctura SA, Campus Biotech Innovation Park, Genève, Switzerland

    Zoe Johnson & Karolina Niewola-Staszkowska

  3. Department of Pathology, University Hospital, School of Medicine, University of Crete, Heraklion, Greece

    Maria Tzardi

  4. Department of Surgical Oncology, University Hospital, School of Medicine, University of Crete, Heraklion, Greece

    Eelco de Bree

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Contributions

EG and AT performed in vitro experiments and experiments with mice and data analyses and drafted the manuscript. LX performed in vitro experiments on cells and mice blood. MT performed histology and interpreted histopathology and immunohistochemistry. Clinical samples and clinical information were obtained from EDB. ZJ, KNS, and EAP conceived the project. EAP designed and analysed the experiments, supervised the research and wrote the paper.

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Correspondence to Evangelia A. Papakonstanti.

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Competing interests

The following authors are or have been employed by and/or share holders of iOnctura: KNS and ZJ. EAP have received research funding from iOnctura. EG and AT have received fees for providing services to this work. The other authors declare no conflict of interest relating to this work. EAP, EG and AT have no additional financial interests.

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Goulielmaki, E., Tsapara, A., Xenou, L. et al. IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03073-3

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  • Received: 28 October 2025

  • Revised: 26 February 2026

  • Accepted: 10 March 2026

  • Published: 27 March 2026

  • DOI: https://doi.org/10.1038/s41420-026-03073-3

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