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

Thomas Bohnacker, Andrea E. Prota, Florent Beaufils, John E. Burke, Anna Melone, Alison J. Inglis, Denise Rageot, Alexander M. Sele, Vladimir Cmiljanovic, Natasa Cmiljanovic, Katja Bargsten, Amol Aher, Anna Akhmanova, J. Fernando Díaz, Doriano Fabbro, Marketa Zvelebil, Roger L. Williams, Michel O. Steinmetz and Matthias P. Wymann ()
Additional contact information
Thomas Bohnacker: University of Basel
Andrea E. Prota: Laboratory of Biomolecular Research, Paul Scherrer Institut
Florent Beaufils: University of Basel
John E. Burke: University of Victoria
Anna Melone: University of Basel
Alison J. Inglis: MRC Laboratory of Molecular Biology
Denise Rageot: University of Basel
Alexander M. Sele: University of Basel
Vladimir Cmiljanovic: University of Basel
Natasa Cmiljanovic: University of Basel
Katja Bargsten: Laboratory of Biomolecular Research, Paul Scherrer Institut
Amol Aher: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht
Anna Akhmanova: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht
J. Fernando Díaz: CIB Centro de Investigaciones Biológicas
Doriano Fabbro: PIQUR Therapeutics AG
Marketa Zvelebil: The Institute of Cancer Research
Roger L. Williams: MRC Laboratory of Molecular Biology
Michel O. Steinmetz: Laboratory of Biomolecular Research, Paul Scherrer Institut
Matthias P. Wymann: University of Basel

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14683

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