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

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dc.contributor.authorBohnacker, Thomas
dc.contributor.authorProta, Andrea E.
dc.contributor.authorBeaufils, Florent
dc.contributor.authorBurke, John E.
dc.contributor.authorMelone, Anna
dc.contributor.authorInglis, Alison J.
dc.contributor.authorRageot, Denise
dc.contributor.authorSele, Alexander M.
dc.contributor.authorCmiljanovic, Vladimir
dc.contributor.authorCmiljanovic, Natasa
dc.contributor.authorBargsten, Katja
dc.contributor.authorAher, Amol
dc.contributor.authorAkhmanova, Anna
dc.contributor.authorDíaz, J. Fernando
dc.contributor.authorFabbro, Doriano
dc.contributor.authorZvelebil, Marketa
dc.contributor.authorWilliams, Roger L.
dc.contributor.authorSteinmetz, Michel O.
dc.contributor.authorWymann, Matthias P.
dc.date.accessioned2018-08-07T19:58:33Z
dc.date.available2018-08-07T19:58:33Z
dc.date.copyright2017en_US
dc.date.issued2017-03
dc.description.abstractBKM120 (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.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipWe thank P. Hebeisen, B. Giese, A. Pfaltz, E. Jackson and J. B. Langlois for advice, discussion and synthesis of chemical precursors and compounds; M. Neubauer and D. Hausinger for chemical structure determination; Pascal Lorenz and the BioOptics Facility for support with microscopy; Robert Ivanek for bioinformatics support and R. Sriramaratnam for editorial help. We are grateful to G. Zaman and the NTRC team for help and expertise with high-content screening assays. This work was supported by the Swiss Commission for Technology and Innovation (CTI) by PFLS-LS grants 14032.1, 15811.2 and 17241.1; the Stiftung fur Krebsbekampfung grant 341, Swiss National Science Foundation grants 310030_153211 and 316030_133860 (to M.P.W.), and 310030B_138659 and 31003A_166608 (to M.O.S.); in part by European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 675392, and grants BIO2013-42984-R (Ministerio de Economia y Competitividad), S2010/BMD-2457 BIPEDD2 (Comunidad Auto noma de Madrid) to J.F.D.; and by the MRC to R.L.W. (U105184308).en_US
dc.identifier.citationBohnacker, T.; Prota, A.E.; Beaufils, F.; Burke, J.E.; Melone, A.; Inglis, A.J.; … & Wymann, M.P. (2017). Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nature Communications, 8, article 14683. https://doi.org/10.1038/ncomms14683en_US
dc.identifier.urihttps://doi.org/10.1038/ncomms14683
dc.identifier.urihttp://hdl.handle.net/1828/9872
dc.language.isoenen_US
dc.publisherNature Communicationsen_US
dc.subject.departmentDepartment of Biochemistry and Microbiology
dc.titleDeconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic interventionen_US
dc.typeArticleen_US

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