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ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors

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Summary

Introduction Wee1 is an important kinase involved in the G2 cell cycle checkpoint and frequently upregulated in intracranial neoplasms such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). Two small molecules are available that target Wee1, AZD1775 and PD0166285, and clinical trials with AZD1775 have already been started. Since GBM and DIPG are highly invasive brain tumors, they are at least to some extent protected by the blood-brain barrier (BBB) and its ATP-binding cassette (ABC) efflux transporters. Methods We have here conducted a comprehensive set of in vitro and in vivo experiments to determine to what extent two dominant efflux transporters in the BBB, P-gp (ABCB1) and BCRP (ABCG2), exhibit affinity towards AZD1775 and PD0166285 and restrict their brain penetration. Results Using these studies, we demonstrate that AZD1775 is efficiently transported by both P-gp and BCRP, whereas PD0166285 is only a substrate of P-gp. Nonetheless, the brain penetration of both compounds was severely restricted in vivo, as indicated by a 5-fold (PD0166285) and 25-fold (AZD1775) lower brain-plasma ratio in wild type mice compared to Abcb1a/b;Abcg2−/− mice. Conclusion The brain penetration of these Wee1 inhibitors is severely limited by ABC transporters, which may compromise their clinical efficacy against intracranial neoplasms such as DIPG and GBM.

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Funding

This work was supported by a research grant from the foundation Stophersentumoren.nl to Olaf van Tellingen.

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Authors and Affiliations

  1. Division of Pharmacology, room H3.014, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands

    Mark C. de Gooijer, Levi C. M. Buil, Jos H. Beijnen & Olaf van Tellingen

  2. Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands

    Mark C. de Gooijer, Levi C. M. Buil & Olaf van Tellingen

  3. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute /Slotervaart Hospital, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands

    Jos H. Beijnen

  4. Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands

    Jos H. Beijnen

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  1. Mark C. de Gooijer
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Correspondence to Olaf van Tellingen.

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Author Mark de Gooijer declares he has no conflicts of interest. Author Levi Buil declares he has no conflicts of interest. Author Jos H. Beijnen declares he has no conflicts of interest. Author Olaf van Tellingen declares he has no conflicts of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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de Gooijer, M.C., Buil, L.C.M., Beijnen, J.H. et al. ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors. Invest New Drugs 36, 380–387 (2018). https://doi.org/10.1007/s10637-017-0539-8

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