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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Bohnacker T,Prota AE,Beaufils F,Burke JE,Melone A,Inglis AJ,Rageot D,Sele AM,Cmiljanovic V,Cmiljanovic N,Bargsten K,Aher A,Akhmanova A,Díaz JF,Fabbro D,Zvelebil M,Williams RL,Steinmetz MO,Wymann MP

doi

10.1038/ncomms14683

subject

Has Abstract

pub_date

2017-03-09 00:00:00

pages

14683

issn

2041-1723

pii

ncomms14683

journal_volume

8

pub_type

杂志文章
  • Implications of improved representations of plant respiration in a changing climate.

    abstract::Land-atmosphere exchanges influence atmospheric CO2. Emphasis has been on describing photosynthetic CO2 uptake, but less on respiration losses. New global datasets describe upper canopy dark respiration (R d) and temperature dependencies. This allows characterisation of baseline R d, instantaneous temperature response...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-017-01774-z

    authors: Huntingford C,Atkin OK,Martinez-de la Torre A,Mercado LM,Heskel MA,Harper AB,Bloomfield KJ,O'Sullivan OS,Reich PB,Wythers KR,Butler EE,Chen M,Griffin KL,Meir P,Tjoelker MG,Turnbull MH,Sitch S,Wiltshire A,Malhi Y

    更新日期:2017-11-17 00:00:00

  • Scanning STED-FCS reveals spatiotemporal heterogeneity of lipid interaction in the plasma membrane of living cells.

    abstract::The interaction of lipids and proteins plays an important role in plasma membrane bioactivity, and much can be learned from their diffusion characteristics. Here we present the combination of super-resolution STED microscopy with scanning fluorescence correlation spectroscopy (scanning STED-FCS, sSTED-FCS) to characte...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms6412

    authors: Honigmann A,Mueller V,Ta H,Schoenle A,Sezgin E,Hell SW,Eggeling C

    更新日期:2014-11-20 00:00:00

  • Sauropod dinosaur osteoderms from the Late Cretaceous of Madagascar.

    abstract::Osteoderms are bones embedded within the dermis, and are common to select members of most major tetrapod lineages. The largest known animals that bear osteoderms are members of Titanosauria, a diverse clade of sauropod dinosaurs. Here we report on two titanosaur osteoderms recovered from the Upper Cretaceous Maevarano...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms1578

    authors: Curry Rogers K,D'Emic M,Rogers R,Vickaryous M,Cagan A

    更新日期:2011-11-29 00:00:00

  • Local chiral symmetry breaking in triatic liquid crystals.

    abstract::Understanding the behaviour of thermally excited many-particle systems, composed of a single particle type having a well-defined shape and size, is important in condensed matter, notably protein crystallization. Here we observe and explain the origin of local chiral symmetry breaking in a surprisingly simple system of...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms1803

    authors: Zhao K,Bruinsma R,Mason TG

    更新日期:2012-05-01 00:00:00

  • Molar tooth carbonates and benthic methane fluxes in Proterozoic oceans.

    abstract::Molar tooth structures are ptygmatically folded and microspar-filled structures common in early- and mid-Proterozoic (∼2,500-750 million years ago, Ma) subtidal successions, but extremely rare in rocks <750 Ma. Here, on the basis of Mg and S isotopes, we show that molar tooth structures may have formed within sediment...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms10317

    authors: Shen B,Dong L,Xiao S,Lang X,Huang K,Peng Y,Zhou C,Ke S,Liu P

    更新日期:2016-01-07 00:00:00

  • Intensification of the meridional temperature gradient in the Great Barrier Reef following the Last Glacial Maximum.

    abstract::Tropical south-western Pacific temperatures are of vital importance to the Great Barrier Reef (GBR), but the role of sea surface temperatures (SSTs) in the growth of the GBR since the Last Glacial Maximum remains largely unknown. Here we present records of Sr/Ca and δ(18)O for Last Glacial Maximum and deglacial corals...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms5102

    authors: Felis T,McGregor HV,Linsley BK,Tudhope AW,Gagan MK,Suzuki A,Inoue M,Thomas AL,Esat TM,Thompson WG,Tiwari M,Potts DC,Mudelsee M,Yokoyama Y,Webster JM

    更新日期:2014-06-17 00:00:00

  • Synapsin II desynchronizes neurotransmitter release at inhibitory synapses by interacting with presynaptic calcium channels.

    abstract::In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphop...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms2515

    authors: Medrihan L,Cesca F,Raimondi A,Lignani G,Baldelli P,Benfenati F

    更新日期:2013-01-01 00:00:00

  • In vivo time-gated fluorescence imaging with biodegradable luminescent porous silicon nanoparticles.

    abstract::Fluorescence imaging is one of the most versatile and widely used visualization methods in biomedical research. However, tissue autofluorescence is a major obstacle confounding interpretation of in vivo fluorescence images. The unusually long emission lifetime (5-13 μs) of photoluminescent porous silicon nanoparticles...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms3326

    authors: Gu L,Hall DJ,Qin Z,Anglin E,Joo J,Mooney DJ,Howell SB,Sailor MJ

    更新日期:2013-01-01 00:00:00

  • Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD.

    abstract::Niemann-Pick type C disease is a fatal, progressive neurodegenerative disorder caused by loss-of-function mutations in NPC1, a multipass transmembrane glycoprotein essential for intracellular lipid trafficking. We sought to define the cellular machinery controlling degradation of the most common disease-causing mutant...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-018-06115-2

    authors: Schultz ML,Krus KL,Kaushik S,Dang D,Chopra R,Qi L,Shakkottai VG,Cuervo AM,Lieberman AP

    更新日期:2018-09-10 00:00:00

  • Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination.

    abstract::Remyelination occurs after spinal cord injury (SCI) but its functional relevance is unclear. We assessed the necessity of myelin regulatory factor (Myrf) in remyelination after contusive SCI by deleting the gene from platelet-derived growth factor receptor alpha positive (PDGFRα-positive) oligodendrocyte progenitor ce...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-018-05473-1

    authors: Duncan GJ,Manesh SB,Hilton BJ,Assinck P,Liu J,Moulson A,Plemel JR,Tetzlaff W

    更新日期:2018-08-03 00:00:00

  • ER-localized auxin transporter PIN8 regulates auxin homeostasis and male gametophyte development in Arabidopsis.

    abstract::Auxin is a key coordinative signal required for many aspects of plant development and its levels are controlled by auxin metabolism and intercellular auxin transport. Here we find that a member of PIN auxin transporter family, PIN8 is expressed in male gametophyte of Arabidopsis thaliana and has a crucial role in poll...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms1941

    authors: Ding Z,Wang B,Moreno I,Dupláková N,Simon S,Carraro N,Reemmer J,Pěnčík A,Chen X,Tejos R,Skůpa P,Pollmann S,Mravec J,Petrášek J,Zažímalová E,Honys D,Rolčík J,Murphy A,Orellana A,Geisler M,Friml J

    更新日期:2012-07-03 00:00:00

  • Meta-analysis of gut microbiome studies identifies disease-specific and shared responses.

    abstract::Hundreds of clinical studies have demonstrated associations between the human microbiome and disease, yet fundamental questions remain on how we can generalize this knowledge. Results from individual studies can be inconsistent, and comparing published data is further complicated by a lack of standard processing and a...

    journal_title:Nature communications

    pub_type: 杂志文章,meta分析

    doi:10.1038/s41467-017-01973-8

    authors: Duvallet C,Gibbons SM,Gurry T,Irizarry RA,Alm EJ

    更新日期:2017-12-05 00:00:00

  • Scattering-type scanning near-field optical microscopy with low-repetition-rate pulsed light source through phase-domain sampling.

    abstract::Scattering-type scanning near-field optical microscopy (s-SNOM) allows spectroscopic imaging with spatial resolution below the diffraction limit. With suitable light sources, s-SNOM is instrumental in numerous discoveries at the nanoscale. So far, the light sources have been limited to continuous wave or high-repetiti...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms13212

    authors: Wang H,Wang L,Xu XG

    更新日期:2016-10-17 00:00:00

  • A mouse model of adult-onset anaemia due to erythropoietin deficiency.

    abstract::Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when th...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms2950

    authors: Yamazaki S,Souma T,Hirano I,Pan X,Minegishi N,Suzuki N,Yamamoto M

    更新日期:2013-01-01 00:00:00

  • The nuclear pore complex prevents sister chromatid recombination during replicative senescence.

    abstract::The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage. Here, we uncover that fusing a DNA binding domain to the NPC basket protein Nup1 reduces telomere relocalization to nuclear pores early after telomerase inactivation. This Nup1 modification also impairs the reloc...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-019-13979-5

    authors: Aguilera P,Whalen J,Minguet C,Churikov D,Freudenreich C,Simon MN,Géli V

    更新日期:2020-01-09 00:00:00

  • The origin and adaptive evolution of domesticated populations of yeast from Far East Asia.

    abstract::The yeast Saccharomyces cerevisiae has been an essential component of human civilization because of its long global history of use in food and beverage fermentation. However, the diversity and evolutionary history of the domesticated populations of the yeast remain elusive. We show here that China/Far East Asia is lik...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-018-05106-7

    authors: Duan SF,Han PJ,Wang QM,Liu WQ,Shi JY,Li K,Zhang XL,Bai FY

    更新日期:2018-07-12 00:00:00

  • C-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation.

    abstract::The ubiquitin receptors Rad23 and Dsk2 deliver polyubiquitylated substrates to the proteasome for destruction. The C-terminal ubiquitin-associated (UBA) domain of Rad23 functions as a cis-acting stabilization signal that protects this protein from proteasomal degradation. Here, we provide evidence that the C-terminal ...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms1179

    authors: Heinen C,Acs K,Hoogstraten D,Dantuma NP

    更新日期:2011-02-08 00:00:00

  • DHX36 prevents the accumulation of translationally inactive mRNAs with G4-structures in untranslated regions.

    abstract::Translation efficiency can be affected by mRNA stability and secondary structures, including G-quadruplex structures (G4s). The highly conserved DEAH-box helicase DHX36/RHAU resolves G4s on DNA and RNA in vitro, however a systems-wide analysis of DHX36 targets and function is lacking. We map globally DHX36 binding to ...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-019-10432-5

    authors: Sauer M,Juranek SA,Marks J,De Magis A,Kazemier HG,Hilbig D,Benhalevy D,Wang X,Hafner M,Paeschke K

    更新日期:2019-06-03 00:00:00

  • Crystallization of DNA-coated colloids.

    abstract::DNA-coated colloids hold great promise for self-assembly of programmed heterogeneous microstructures, provided they not only bind when cooled below their melting temperature, but also rearrange so that aggregated particles can anneal into the structure that minimizes the free energy. Unfortunately, DNA-coated colloids...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms8253

    authors: Wang Y,Wang Y,Zheng X,Ducrot É,Yodh JS,Weck M,Pine DJ

    更新日期:2015-06-16 00:00:00

  • Human microcephaly protein RTTN interacts with STIL and is required to build full-length centrioles.

    abstract::Mutations in many centriolar protein-encoding genes cause primary microcephaly. Using super-resolution and electron microscopy, we find that the human microcephaly protein, RTTN, is recruited to the proximal end of the procentriole at early S phase, and is located at the inner luminal walls of centrioles. Further stud...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-017-00305-0

    authors: Chen HY,Wu CT,Tang CC,Lin YN,Wang WJ,Tang TK

    更新日期:2017-08-15 00:00:00

  • Expansion of the Tibetan Plateau during the Neogene.

    abstract::The appearance of detritus shed from mountain ranges along the northern margin of the Tibetan Plateau heralds the Cenozoic development of high topography. Current estimates of the age of the basal conglomerate in the Qaidam basin place this event in Paleocene-Eocene. Here we present new magnetostratigraphy and mammali...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms15887

    authors: Wang W,Zheng W,Zhang P,Li Q,Kirby E,Yuan D,Zheng D,Liu C,Wang Z,Zhang H,Pang J

    更新日期:2017-06-21 00:00:00

  • Selective hydrogenation of 5-(hydroxymethyl)furfural to 5-methylfurfural over single atomic metals anchored on Nb2O5.

    abstract::5-Methylfurfural (MF) is a very useful chemical. Selective hydrogenation of biomass platform molecule 5-(hydroxymethyl)furfural (HMF) to MF using H2 as the reducing agent is very attractive, but challenging because hydrogenation of C=O bond in HMF is more favourable than C-OH both kinetically and thermodynamically, an...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-020-20878-7

    authors: Li S,Dong M,Yang J,Cheng X,Shen X,Liu S,Wang ZQ,Gong XQ,Liu H,Han B

    更新日期:2021-01-26 00:00:00

  • Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation.

    abstract::Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in th...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms9164

    authors: Ryu JK,Petersen MA,Murray SG,Baeten KM,Meyer-Franke A,Chan JP,Vagena E,Bedard C,Machado MR,Rios Coronado PE,Prod'homme T,Charo IF,Lassmann H,Degen JL,Zamvil SS,Akassoglou K

    更新日期:2015-09-10 00:00:00

  • Source identification and distribution reveals the potential of the geochemical Antarctic sea ice proxy IPSO25.

    abstract::The presence of a di-unsaturated highly branched isoprenoid (HBI) lipid biomarker (diene II) in Southern Ocean sediments has previously been proposed as a proxy measure of palaeo Antarctic sea ice. Here we show that a source of diene II is the sympagic diatom Berkeleya adeliensis Medlin. Furthermore, the propensity fo...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms12655

    authors: Belt ST,Smik L,Brown TA,Kim JH,Rowland SJ,Allen CS,Gal JK,Shin KH,Lee JI,Taylor KW

    更新日期:2016-08-30 00:00:00

  • Ribosome engineering reveals the importance of 5S rRNA autonomy for ribosome assembly.

    abstract::5S rRNA is an indispensable component of cytoplasmic ribosomes in all species. The functions of 5S rRNA and the reasons for its evolutionary preservation as an independent molecule remain unclear. Here we used ribosome engineering to investigate whether 5S rRNA autonomy is critical for ribosome function and cell survi...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-020-16694-8

    authors: Huang S,Aleksashin NA,Loveland AB,Klepacki D,Reier K,Kefi A,Szal T,Remme J,Jaeger L,Vázquez-Laslop N,Korostelev AA,Mankin AS

    更新日期:2020-06-09 00:00:00

  • Excited-state vibrational dynamics toward the polaron in methylammonium lead iodide perovskite.

    abstract::Hybrid organic-inorganic perovskites have attractive optoelectronic properties including exceptional solar cell performance. The improved properties of perovskites have been attributed to polaronic effects involving stabilization of localized charge character by structural deformations and polarizations. Here we exami...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-018-04946-7

    authors: Park M,Neukirch AJ,Reyes-Lillo SE,Lai M,Ellis SR,Dietze D,Neaton JB,Yang P,Tretiak S,Mathies RA

    更新日期:2018-06-28 00:00:00

  • Interleukin-36 cytokines alter the intestinal microbiome and can protect against obesity and metabolic dysfunction.

    abstract::Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found i...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/s41467-019-11944-w

    authors: Giannoudaki E,Hernandez-Santana YE,Mulfaul K,Doyle SL,Hams E,Fallon PG,Mat A,O'Shea D,Kopf M,Hogan AE,Walsh PT

    更新日期:2019-09-05 00:00:00

  • Fast nanoscale addressability of nitrogen-vacancy spins via coupling to a dynamic ferromagnetic vortex.

    abstract::The core of a ferromagnetic vortex domain creates a strong, localized magnetic field, which can be manipulated on nanosecond timescales, providing a platform for addressing and controlling individual nitrogen-vacancy centre spins in diamond at room temperature, with nanometre-scale resolution. Here, we show that the f...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms11584

    authors: Wolf MS,Badea R,Berezovsky J

    更新日期:2016-06-14 00:00:00

  • Marine sequestration of carbon in bacterial metabolites.

    abstract::Linking microbial metabolomics and carbon sequestration in the ocean via refractory organic molecules has been hampered by the chemical complexity of dissolved organic matter (DOM). Here, using bioassay experiments and ultra-high resolution metabolic profiling, we demonstrate that marine bacteria rapidly utilize simpl...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms7711

    authors: Lechtenfeld OJ,Hertkorn N,Shen Y,Witt M,Benner R

    更新日期:2015-03-31 00:00:00

  • Electronic origin of high-temperature superconductivity in single-layer FeSe superconductor.

    abstract::The recent discovery of high-temperature superconductivity in iron-based compounds has attracted much attention. How to further increase the superconducting transition temperature (T(c)) and how to understand the superconductivity mechanism are two prominent issues facing the current study of iron-based superconductor...

    journal_title:Nature communications

    pub_type: 杂志文章

    doi:10.1038/ncomms1946

    authors: Liu D,Zhang W,Mou D,He J,Ou YB,Wang QY,Li Z,Wang L,Zhao L,He S,Peng Y,Liu X,Chen C,Yu L,Liu G,Dong X,Zhang J,Chen C,Xu Z,Hu J,Chen X,Ma X,Xue Q,Zhou XJ

    更新日期:2012-07-03 00:00:00