title: Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.
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.
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bohnacker
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Prota
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Florent
authors.initials: F
authors.lastname: Beaufils
authors.affiliation: Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia BC V8W 2Y2, Canada.
authors.forename: John E
authors.identifier: 0000-0001-7904-9859
authors.initials: JE
authors.lastname: Burke
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Melone
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Inglis
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Rageot
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Sele
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Cmiljanovic
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Natasa
authors.initials: N
authors.lastname: Cmiljanovic
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Bargsten
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.
authors.forename: Amol
authors.initials: A
authors.lastname: Aher
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.
authors.forename: Anna
authors.identifier: 0000-0002-9048-8614
authors.initials: A
authors.lastname: Akhmanova
authors.affiliation: CIB Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.affiliation: PIQUR Therapeutics AG, 4057 Basel, Switzerland.
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.affiliation: The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; C571178:NVP-BKM120