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Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases

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Summary

Inhibitors of PI3K signaling are of great therapeutic interest in oncology. The phosphoinositide-3-kinase signaling pathway is activated in a variety of solid and non-solid tumors. We have identified an imidazopyrazine derivative, ETP-46321, as a potent inhibitor of PI3Kα \( {\text{K}}_{\text{i}}^{\text{app}} = {2}.{\text{4 nM}} \). The compound was 6 times less potent towards PI3Kδ and more than 200 and 60 times less potent at inhibiting PI3Kβ and PI3Kγ and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC50’s > 5 μM), or an additional 287 protein kinases that were screened. ETP-46321 inhibited PI3K signaling in treated tumor cell lines, induced cell cycle arrest and inhibited VEGF-dependent sprouting of HUVEC cells. The compound was anti-proliferative and synergized with both cytotoxic and targeted therapeutics. The compound induced a reduction in the phosphorylation of Akt in U87 MG xenografts after a single treatment. The growth of colon and lung cancinoma HT-29 and A549 xenografts was delayed by once a day treatment with ETP-46321. The compound synergized with Doxotaxel in a model of ovarian cancer.

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Abbreviations

PI3K:

phosphoinositide 3-kinase

GFP:

green fluorescent protein

PTEN:

phosphatase and tensin homolog

FOXO:

Forkhead box O

mTOR:

mammalian target of rapamycin

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Acknowledgements

The authors would like to thank members of the Histology and Immunohistochemistry Core Unit at the Spanish National Cancer Research Centre for the immunohistochemistry images and quantification presented in Fig. 3. The work reported in this manuscript was funded by the Spanish Ministry of Science and Innovation (MICINN) through the project CIT-090100-2007-48.

Conflict of interest statement

T. G. G., D. C., S. M., P. V. A, E. C. L., W. L., T. M., B. G. S., S. P., I. P., M. I. A., A. C., M. L., P. A., J. P. and J. P. declare no conflicts of interest A. R. L. is an employee of Astex Pharmaceuticals. J. R. B. is an employee of Janssen Pharmaceutical Companies of Johnson & Johnson.

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Author notes

  1. Teresa G. Granda

    Present address: Health Research Institut Biocruces, Cruces Hospital, Plaza Cruces s/n, Baracaldo, 48903, Spain

  2. Ana Rodríguez López

    Present address: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK

  3. James R. Bischoff

    Present address: Janssen Pharmaceutica, Department of Oncology, Janssen Research and Development, Turnhoutseweg 30, Beerse, 2340, Belgium

Authors and Affiliations

  1. Experimental Therapeutics Programme, Spanish National Cancer Research Centre, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain

    David Cebrián, Sonia Martínez, Patricia Villanueva Anguita, Estela Casas López, Wolfgang Link, Teresa Merino, Joaquín Pastor, Beatriz G. Serelde, Sandra Peregrina, Irene Palacios, Maria Isabel Albarran, Antonio Cebriá, Milagros Lorenzo, Patricia Alonso & Jesús Fominaya

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Granda, T.G., Cebrián, D., Martínez, S. et al. Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases. Invest New Drugs 31, 66–76 (2013). https://doi.org/10.1007/s10637-012-9835-5

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