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2018 ; 8
(1
): 10784
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Buparlisib is a brain penetrable pan-PI3K inhibitor
#MMPMID30018387
de Gooijer MC
; Zhang P
; Buil LCM
; Çitirikkaya CH
; Thota N
; Beijnen JH
; van Tellingen O
Sci Rep
2018[Jul]; 8
(1
): 10784
PMID30018387
show ga
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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