Buparlisib is a brain penetrable pan-PI3K inhibitor

Scientific Reports
Mark C de GooijerOlaf van Tellingen

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.

References

Oct 19, 2000·Journal of the National Cancer Institute·J W JonkerA H Schinkel
Nov 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Johan W JonkerAlfred H Schinkel
Oct 1, 2008·Neuropharmacology·Carlos Luna-TortósWolfgang Löscher
Jul 25, 2009·Nature Reviews. Cancer·Jeffrey A Engelman
Feb 24, 2010·Computer Methods and Programs in Biomedicine·Yong ZhangShaofei Xie
Oct 1, 2010·Science Translational Medicine·Silvia BuonamiciMarion Dorsch
Nov 9, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dimpy KoulW K Alfred Yung
Dec 14, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Johanna C BendellJosé Baselga
Dec 23, 2011·Molecular Cancer Therapeutics·Sauveur-Michel MairaCharles F Voliva
Sep 21, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Laurent SalphatiHeidi S Phillips
Oct 15, 2013·Cell·Cameron W BrennanUNKNOWN TCGA Research Network
Feb 1, 2014·Nature Reviews. Drug Discovery·David A Fruman, Christian Rommel
Dec 24, 2014·Nature Reviews. Cancer·Lauren M ThorpeJean J Zhao
Feb 3, 2015·Advances in Cancer Research·Selvi DurmusAlfred H Schinkel
Mar 21, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·O van TellingenH E de Vries
Apr 15, 2015·International Journal of Cancer. Journal International Du Cancer·Ping ZhangOlaf van Tellingen
Jun 20, 2015·Cell·UNKNOWN Cancer Genome Atlas Network
Apr 21, 2016·ACS Medicinal Chemistry Letters·Timothy P HeffronAlan G Olivero
Nov 3, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Heike NiessnerFriedegund Meier
Aug 16, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Matthias OsswaldFrank Winkler
Aug 25, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Fan LinOlaf van Tellingen
Nov 1, 2016·Nature·Megan M KanedaJudith A Varner
Jun 7, 2017·Nature Communications·Choi-Fong ChoSean E Lawler
Oct 19, 2017·Nature Communications·Mayuko UeharaReza Abdi

❮ Previous
Next ❯

Citations

Sep 1, 2019·International Journal of Molecular Sciences·Synnøve Nymark AasenFrits Thorsen
Mar 13, 2020·Expert Opinion on Pharmacotherapy·Dirk L Kienle, Stephan Stilgenbauer
Apr 11, 2020·Breast Cancer Research and Treatment·Pamela R Drullinsky, Sara A Hurvitz
Mar 17, 2019·International Journal of Molecular Sciences·Malcolm LimJodi M Saunus
Mar 25, 2020·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·I MeattiniO Kaidar Person
Oct 14, 2020·The Journal of Cell Biology·S Joseph EndicottRichard A Miller
Feb 24, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Franziska M IppenPriscilla K Brastianos
Mar 13, 2019·ACS Applied Materials & Interfaces·Allison N DuRossConroy Sun
Oct 31, 2021·Drug Delivery and Translational Research·Christine P CarneyAnthony J Kim
Oct 8, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Caitlin M StewartConnie Lee Batlevi

❮ Previous
Next ❯

Clinical Trials Mentioned

NCT02000882
NCT02452294
NCT01339052
NCT01633060
NCT02756247

Software Mentioned

SPSS
Analyst

Related Concepts

Related Feeds

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.

Blood-Brain Barrier Transport in Neurodegeneration

The blood brain barrier is important for regulating the movement of biomolecules in and out of the brain. For example, membrane transporters in the blood brain barrier can be essential for regulating drug movement and dysregulation of these processes may play a role in neurodegeneration. This feed follows the latest research on this topic.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.