Buparlisib is a brain penetrable pan-PI3K inhibitor

Mark C De Gooijer,Nishita Thota,Jos H Beijnen,Levi C M Buil,Ceren H Çitirikkaya,Ping Zhang,Olaf Van Tellingen

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.

Highlights

Phosphatidylinositol 3-kinase (PI3K) is a key component of the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway and as such important for cell proliferation and survival[1]
The brain penetration of a small molecular compound is generally restricted by the blood-brain barrier (BBB), which is composed of the brain endothelial cells (BECs) that are being supported by astrocytes and pericytes[15]
We first sought to investigate whether buparlisib (Fig. 1A) is transported by P-gp or breast cancer resistance protein (BCRP) in vitro using concentration equilibrium transport assays (CETAs)

Summary

Introduction

Phosphatidylinositol 3-kinase (PI3K) is a key component of the PI3K-AKT-mTOR pathway and as such important for cell proliferation and survival[1]. It is important to assess whether a PI3K inhibitor has sufficient brain penetration prior to starting its development for treatment of intracranial cancers. BECs abundantly express ATP-binding cassette (ABC) efflux transporters on their apical membranes that very efficiently pump xenobiotics back into the bloodstream, thereby protecting the brain parenchyma from potentially harmful substances. Among these transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the most dominant. Buparlisib is a novel pan-PI3K inhibitor that has been developed to inhibit all class I PI3K isoforms[17] It has shown preclinical efficacy in various PI3K pathway overactivated cancer models, including GBM18–20. Is being tested in primary and secondary intracranial cancers (e.g., ClinicalTrials.gov Identifiers NCT02000882, NCT02452294, NCT01339052)

Methods

Results

Conclusion