An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.

Abstract:

:The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.

journal_name

Nature

journal_title

Nature

authors

Soucy TA,Smith PG,Milhollen MA,Berger AJ,Gavin JM,Adhikari S,Brownell JE,Burke KE,Cardin DP,Critchley S,Cullis CA,Doucette A,Garnsey JJ,Gaulin JL,Gershman RE,Lublinsky AR,McDonald A,Mizutani H,Narayanan U,Olhava EJ

doi

10.1038/nature07884

subject

Has Abstract

pub_date

2009-04-09 00:00:00

pages

732-6

issue

7239

eissn

0028-0836

issn

1476-4687

pii

nature07884

journal_volume

458

pub_type

杂志文章

相关文献

NATURE文献大全
  • The landscape of somatic mutation in normal colorectal epithelial cells.

    abstract::The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal ti...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-019-1672-7

    authors: Lee-Six H,Olafsson S,Ellis P,Osborne RJ,Sanders MA,Moore L,Georgakopoulos N,Torrente F,Noorani A,Goddard M,Robinson P,Coorens THH,O'Neill L,Alder C,Wang J,Fitzgerald RC,Zilbauer M,Coleman N,Saeb-Parsy K,Martincorena

    更新日期:2019-10-01 00:00:00

  • Monoclonal antibody production by receptor-mediated electrically induced cell fusion.

    abstract::Fusion of myeloma cells and B lymphocytes to form hybridomas which produce monoclonal antibodies has been a major advance, but the poor efficiency and randomness of viral or polyethylene glycol fusion techniques generally gives poor yields of specific, high affinity antibodies. High voltage electrical fields with diel...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/310792a0

    authors: Lo MM,Tsong TY,Conrad MK,Strittmatter SM,Hester LD,Snyder SH

    更新日期:1984-08-30 00:00:00

  • Context-dependent autonomous self-fertilization yields reproductive assurance and mixed mating.

    abstract::The evolution of self-fertilization in hermaphrodites is opposed by costs that decrease the value of self progeny relative to that of outcross progeny. However, self-fertilization is common in plants; 20% are highly selfing and 33% are intermediate between selfing and outcrossing. Darwin proposed an adaptive benefit o...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02776

    authors: Kalisz S,Vogler DW,Hanley KM

    更新日期:2004-08-19 00:00:00

  • Is the guinea-pig a rodent?

    abstract::The guinea-pig (Cavia porcellus), traditionally classified as a New World hystricomorph rodent, often shows anomalous morphological and molecular features in comparison with other eutherian mammals. For example, its insulin differs from that of other mammals in anabolic and growth-promoting activities and in its capab...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/351649a0

    authors: Graur D,Hide WA,Li WH

    更新日期:1991-06-20 00:00:00

  • NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.

    abstract::Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it r...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature11729

    authors: Heneka MT,Kummer MP,Stutz A,Delekate A,Schwartz S,Vieira-Saecker A,Griep A,Axt D,Remus A,Tzeng TC,Gelpi E,Halle A,Korte M,Latz E,Golenbock DT

    更新日期:2013-01-31 00:00:00

  • Molecular logic behind the three-way stochastic choices that expand butterfly colour vision.

    abstract::Butterflies rely extensively on colour vision to adapt to the natural world. Most species express a broad range of colour-sensitive Rhodopsin proteins in three types of ommatidia (unit eyes), which are distributed stochastically across the retina. The retinas of Drosophila melanogaster use just two main types, in whic...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature18616

    authors: Perry M,Kinoshita M,Saldi G,Huo L,Arikawa K,Desplan C

    更新日期:2016-07-14 00:00:00

  • Reassortment of pilin genes in Neisseria gonorrhoeae occurs by two distinct mechanisms.

    abstract::Phase and antigenic variation of pilin expression in Neisseria gonorrhoeae result from recombination events in which variant sequences from one of the silent loci (pilS) are transferred to the expression locus (pilE). Such rearrangements were originally thought to be gene conversions, but findings showing that phase v...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/338651a0

    authors: Gibbs CP,Reimann BY,Schultz E,Kaufmann A,Haas R,Meyer TF

    更新日期:1989-04-20 00:00:00

  • Geometry-induced electrostatic trapping of nanometric objects in a fluid.

    abstract::The ability to trap an object-whether a single atom or a macroscopic entity-affects fields as diverse as quantum optics, soft condensed-matter physics, biophysics and clinical medicine. Many sophisticated methodologies have been developed to counter the randomizing effect of Brownian motion in solution, but stable tra...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09404

    authors: Krishnan M,Mojarad N,Kukura P,Sandoghdar V

    更新日期:2010-10-07 00:00:00

  • Hox protein mutation and macroevolution of the insect body plan.

    abstract::A fascinating question in biology is how molecular changes in developmental pathways lead to macroevolutionary changes in morphology. Mutations in homeotic (Hox) genes have long been suggested as potential causes of morphological evolution, and there is abundant evidence that some changes in Hox expression patterns co...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature716

    authors: Ronshaugen M,McGinnis N,McGinnis W

    更新日期:2002-02-21 00:00:00

  • Structural analysis of murine genes containing homoeo box sequences and their expression in embryonal carcinoma cells.

    abstract::The presence of homoeo box sequences in the genomes of vertebrates has suggested that these metazoans possess the equivalent of the homoeotic genes that have a key role in regulating the development of the fruitfly Drosophila melanogaster. We report here that a novel murine homoeo box-containing gene is expressed in e...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/314713a0

    authors: Colberg-Poley AM,Voss SD,Chowdhury K,Gruss P

    更新日期:1985-04-25 00:00:00

  • Enkephalin-, VIP- and substance P-like immunoreactivity in the carotid body.

    abstract::The carotid body type I cell contains amines and has features, both morphological and cytochemical, which indicate that it may also produce a peptide. Many regulatory peptides are now known to be present in both central and peripheral tissues. In the periphery these neuropeptides occur in both classical endocrine (APU...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/284269a0

    authors: Wharton J,Polak JM,Pearse AG,McGregor GP,Bryant MG,Bloom SR,Emson PC,Bisgard GE,Will JA

    更新日期:1980-03-20 00:00:00

  • A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials.

    abstract::Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties, their preparation is often com...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature14902

    authors: Parr BT,Economou C,Herzon SB

    更新日期:2015-09-24 00:00:00

  • The Polycomb group protein EZH2 directly controls DNA methylation.

    abstract::The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins and the DNA methylation systems. Here we show that the corresponding silencing pathw...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature04431

    authors: Viré E,Brenner C,Deplus R,Blanchon L,Fraga M,Didelot C,Morey L,Van Eynde A,Bernard D,Vanderwinden JM,Bollen M,Esteller M,Di Croce L,de Launoit Y,Fuks F

    更新日期:2006-02-16 00:00:00

  • Pre-bending of a promoter sequence enhances affinity for the TATA-binding factor.

    abstract::TATA-binding protein (TBP) binds the minor groove of the TATA element with the DNA bent 80 degrees towards the major groove. A constrained minicircle strategy has been used to test the effect of DNA topology on the affinity of TBP for the TATA element. We report here that TBP bound to DNA which was slightly pre-bent t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/373724a0

    authors: Parvin JD,McCormick RJ,Sharp PA,Fisher DE

    更新日期:1995-02-23 00:00:00

  • Practical quantum key distribution protocol without monitoring signal disturbance.

    abstract::Quantum cryptography exploits the fundamental laws of quantum mechanics to provide a secure way to exchange private information. Such an exchange requires a common random bit sequence, called a key, to be shared secretly between the sender and the receiver. The basic idea behind quantum key distribution (QKD) has wide...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature13303

    authors: Sasaki T,Yamamoto Y,Koashi M

    更新日期:2014-05-22 00:00:00

  • The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice.

    abstract::Transgenic mice bearing the cellular myc oncogene coupled to the immunoglobulin mu or kappa enhancer frequently develop a fatal lymphoma within a few months of birth. Since the tumours represent represent both immature and mature B lymphocytes, constitutive c-myc expression appears to be highly leukaemogenic at severa...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/318533a0

    authors: Adams JM,Harris AW,Pinkert CA,Corcoran LM,Alexander WS,Cory S,Palmiter RD,Brinster RL

    更新日期:1985-12-12 00:00:00

  • Transposon tagging of a male sterility gene in Arabidopsis.

    abstract::Transformation of the well-studied maize transposable elements into other plant species should enable transposon tagging methodology to be used for the isolation of interesting genes in the heterologous host. Here we describe the isolation of a transposon-tagged male sterile mutant in Arabidopsis thaliana using the ma...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/363715a0

    authors: Aarts MG,Dirkse WG,Stiekema WJ,Pereira A

    更新日期:1993-06-24 00:00:00

  • Precise climate monitoring using complementary satellite data sets

    abstract::Observations from Earth-orbiting satellites have been a key component in monitoring climate change for the past two decades. This has become possible with the availability of air temperatures from the Microwave Sounding Unit (MSU) since 1979, sea surface temperatures from the Advanced Very High Resolution Radiometer (...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35000184

    authors: Wentz FJ,Schabel M

    更新日期:2000-01-27 00:00:00

  • Information causality as a physical principle.

    abstract::Quantum physics has remarkable distinguishing characteristics. For example, it gives only probabilistic predictions (non-determinism) and does not allow copying of unknown states (no-cloning). Quantum correlations may be stronger than any classical ones, but information cannot be transmitted faster than light (no-sign...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature08400

    authors: Pawłowski M,Paterek T,Kaszlikowski D,Scarani V,Winter A,Zukowski M

    更新日期:2009-10-22 00:00:00

  • Evolution of antibody immunity to SARS-CoV-2.

    abstract::Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models1,2. Antibody ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-021-03207-w

    authors: Gaebler C,Wang Z,Lorenzi JCC,Muecksch F,Finkin S,Tokuyama M,Cho A,Jankovic M,Schaefer-Babajew D,Oliveira TY,Cipolla M,Viant C,Barnes CO,Bram Y,Breton G,Hägglöf T,Mendoza P,Hurley A,Turroja M,Gordon K,Millard KG,

    更新日期:2021-01-18 00:00:00

  • SWI6 protein is required for transcription of the periodically expressed DNA synthesis genes in budding yeast.

    abstract::In budding yeast many genes are expressed under cell-cycle control in late G1. These include a large group of DNA synthesis genes, the HO gene involved in mating-type switching, CTS1 (chitinase) and also CLN1 and CLN2 (ref. 4) encoding G1 cyclins. Two factors, encoded by the SWI4 and SWI6 genes, are required for HO (r...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/357505a0

    authors: Lowndes NF,Johnson AL,Breeden L,Johnston LH

    更新日期:1992-06-11 00:00:00

  • A new antibiotic selectively kills Gram-negative pathogens.

    abstract::The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics that acted against Gram-negative bacteria was deve...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-019-1791-1

    authors: Imai Y,Meyer KJ,Iinishi A,Favre-Godal Q,Green R,Manuse S,Caboni M,Mori M,Niles S,Ghiglieri M,Honrao C,Ma X,Guo JJ,Makriyannis A,Linares-Otoya L,Böhringer N,Wuisan ZG,Kaur H,Wu R,Mateus A,Typas A,Savitski MM,Es

    更新日期:2019-12-01 00:00:00

  • Fully effective contraception in male and female guinea pigs immunized with the sperm protein PH-20.

    abstract::Immunization of male and female animals with extracts of whole sperm cells is known to cause infertility. Also, men and women who spontaneously produce antisperm antibodies are infertile but otherwise healthy. Although the critical sperm antigens are unknown, these observations have led to the proposal that sperm prot...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/335543a0

    authors: Primakoff P,Lathrop W,Woolman L,Cowan A,Myles D

    更新日期:1988-10-06 00:00:00

  • Evolutionary genomics: codon bias and selection on single genomes.

    abstract::The idea that natural selection on genes might be detected using only a single genome has been put forward by Plotkin and colleagues, who present a method that they claim can detect selection without the need for comparative data and which, if correct, would confer greater power of analysis with less information. Here...

    journal_title:Nature

    pub_type: 评论,杂志文章

    doi:10.1038/nature03221

    authors: Hahn MW,Mezey JG,Begun DJ,Gillespie JH,Kern AD,Langley CH,Moyle LC

    更新日期:2005-01-20 00:00:00

  • Structure of a presenilin family intramembrane aspartate protease.

    abstract::Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature11801

    authors: Li X,Dang S,Yan C,Gong X,Wang J,Shi Y

    更新日期:2013-01-03 00:00:00

  • Association of Cdk-activating kinase subunits with transcription factor TFIIH.

    abstract::The RNA polymerase II large subunit contains an essential carboxy-terminal domain (CTD) believed to be involved in the response to regulators during transcription initiation. The CTD is phosphorylated on a portion of RNA polymerase II molecules in vivo and it can be phosphorylated by the general transcription factor T...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/374280a0

    authors: Serizawa H,Mäkelä TP,Conaway JW,Conaway RC,Weinberg RA,Young RA

    更新日期:1995-03-16 00:00:00

  • A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1.

    abstract::Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethali...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-019-1830-y

    authors: Tao P,Sun J,Wu Z,Wang S,Wang J,Li W,Pan H,Bai R,Zhang J,Wang Y,Lee PY,Ying W,Zhou Q,Hou J,Wang W,Sun B,Yang M,Liu D,Fang R,Han H,Yang Z,Huang X,Li H,Deuitch N,Zhang Y,Dissanayake D,Haude K,McWalter K

    更新日期:2020-01-01 00:00:00

  • Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch.

    abstract::The biosynthesis of several protein cofactors is subject to feedback regulation by riboswitches. Flavin mononucleotide (FMN)-specific riboswitches, also known as RFN elements, direct expression of bacterial genes involved in the biosynthesis and transport of riboflavin (vitamin B(2)) and related compounds. Here we pre...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature07642

    authors: Serganov A,Huang L,Patel DJ

    更新日期:2009-03-12 00:00:00

  • Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites.

    abstract::A 12 amino-acid synthetic peptide (NANP)3 comprising the immunodominant epitope of Plasmodium falciparum circumsporozoite protein was conjugated to tetanus toxoid (TT), adjuvanted with aluminium hydroxide, and administered intramuscularly in three doses at monthly intervals to 35 healthy males as a malaria vaccine. No...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/328257a0

    authors: Herrington DA,Clyde DF,Losonsky G,Cortesia M,Murphy JR,Davis J,Baqar S,Felix AM,Heimer EP,Gillessen D

    更新日期:1987-07-16 00:00:00

  • EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.

    abstract::Non-small-cell lung cancer is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer; therefore, alternative drug targets, including epigenetic enzymes, are under consideration f...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature14122

    authors: Fillmore CM,Xu C,Desai PT,Berry JM,Rowbotham SP,Lin YJ,Zhang H,Marquez VE,Hammerman PS,Wong KK,Kim CF

    更新日期:2015-04-09 00:00:00