2. Academic Validation
  3. Buparlisib is a brain penetrable pan-PI3K inhibitor

Buparlisib is a brain penetrable pan-PI3K inhibitor

  • Sci Rep. 2018 Jul 17;8(1):10784. doi: 10.1038/s41598-018-29062-w.
Mark C de Gooijer 1 2,  Ping Zhang 1 2 3,  Levi C M Buil 1 2,  Ceren H Çitirikkaya 1 2,  Nishita Thota 1 2,  Jos H Beijnen 1 4 5,  Olaf van Tellingen 6 7
Affiliations

Affiliations

  • 1 Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 2 Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 3 Department of Neurosurgery, Qilu Hospital, Shandong University, Wenhua Xi Road 107, 250012, Jinan, P.R. China.
  • 4 Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute / MC Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
  • 5 Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
  • 6 Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. [email protected].
  • 7 Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. [email protected].
PMID: 30018387 DOI: 10.1038/s41598-018-29062-w
Abstract

Characterization of the genomic landscapes of intracranial tumours has revealed a clear role for the PI3K-AKT-mTOR pathway in tumorigenesis and tumour maintenance of these malignancies, making phosphatidylinositol 3-kinase (PI3K) inhibition a promising therapeutic strategy for these tumours. Buparlisib is a novel pan-PI3K inhibitor that is currently in clinical development for various cancers, including primary and secondary brain tumours. Importantly however, earlier studies have revealed that sufficient brain penetration is a prerequisite for antitumor efficacy against intracranial tumours. We therefore investigated the brain penetration of buparlisib using a comprehensive set of in vitro and in vivo mouse models. We demonstrate that buparlisib has an excellent brain penetration that is unaffected by efflux transporters at the blood-brain barrier, complete oral bioavailability and efficient intracranial target inhibition at clinically achievable plasma concentrations. Together, these characteristics make buparlisib the ideal candidate for intracranially-targeted therapeutic strategies that involve PI3K inhibition.

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