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

作者：de Gooijer Mark C.; Buil Levi C. M.; Beijnen Jos H.; van Tellingen Olaf^*

来源：Investigational New Drugs, 2018, 36(3): 380-387.

DOI：10.1007/s10637-017-0539-8

• Glioma
• Pharmacokinetics
• Weel
• ABC transporters
• AZD1775
• PD0166285

Introduction Weel 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 Weel, 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 Abcb1 a/b;Abcg2(-/-) mice. Conclusion The brain penetration of these Weel inhibitors is severely limited by ABC transporters, which may compromise their clinical efficacy against intracranial neoplasms such as DIPG and GBM.

• 出版日期2018-6