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

Author

Listed:
  • Thomas Bohnacker

    (University of Basel)

  • Andrea E. Prota

    (Laboratory of Biomolecular Research, Paul Scherrer Institut)

  • Florent Beaufils

    (University of Basel
    Present address: PIQUR Therapeutics AG, 4057 Basel, Switzerland)

  • 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
    Present address: PIQUR Therapeutics AG, 4057 Basel, Switzerland)

  • Natasa Cmiljanovic

    (University of Basel
    Present address: PIQUR Therapeutics AG, 4057 Basel, Switzerland)

  • Katja Bargsten

    (Laboratory of Biomolecular Research, Paul Scherrer Institut
    Present address: Institute of Biochemistry, University of Zürich, 8057 Zürich, Switzerland)

  • 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)

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.

Suggested Citation

  • 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 , 2017. "Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14683
    DOI: 10.1038/ncomms14683
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