Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

Bohnacker, Thomas and Prota, Andrea E. and Beaufils, Florent and Burke, John E. and Melone, Anna and Inglis, Alison J. and Rageot, Denise and Sele, Alexander M. and Cmiljanovic, Vladimir and Cmiljanovic, Natasa and Bargsten, Katja and Aher, Amol and Akhmanova, Anna and Fernando Diaz, J. and Fabbro, Doriano and Zvelebil, Marketa and Williams, Roger L. and Steinmetz, Michel O. and Wymann, Matthias P.. (2017) Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nature communications, 8. p. 14683.

Full text not available from this repository.

Official URL: https://edoc.unibas.ch/62527/

Downloads: Statistics Overview


BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)
UniBasel Contributors:Wymann, Matthias P.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:04 Aug 2020 14:38
Deposited On:04 Aug 2020 14:35

Repository Staff Only: item control page