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

DOI: 10.1038/ncomms14683

Authors: Thomas Bohnacker (University of Basel) , Andrea E. Prota (Paul Scherrer Institut) , Florent Beaufils (University of Basel) , John E. Burke (University of Victoria, Canada) , 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 (Paul Scherrer Institut) , Amol Aher (Utrecht University) , Anna Akhmanova (Utrecht University) , J. Fernando Díaz (CIB Centro de Investigaciones Biologicas) , Doriano Fabbro (PIQUR Therapeutics AG) , Marketa Zvelebil (The Institute of Cancer Research) , Roger L. Williams (MRC Laboratory of Molecular Biology) , Michel O. Steinmetz (Paul Scherrer Institut) , Matthias P. Wymann (University of Basel)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 8

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 8547

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.

Journal Keywords: Drug development; Microtubules; Phosphoinositol signalling; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 30/03/2017 11:14

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)