Outlook |
Featured
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Outlook |
Biomarkers: Portents of malignancy
Being able to determine an individual's chances of developing cancer will greatly improve risk management strategies and recruitment to clinical trials.
- Vicki Brower
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Outlook |
Chemoprevention: First line of defence
Combinations of drugs are showing some promise as therapeutic agents that stop cancer before it starts.
- Lauren Gravitz
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Letter |
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Lung cancers with activating mutations in EGFR can be treated with EGFR inhibitors, but not all tumours respond and some develop resistance. In an RNAi screen, this study searches for modifiers of the EGFR inhibitor response. It is found that inhibition of FAS and NF-κB signalling enhances the response in vitro and in vivo. In a cohort of lung cancer patients treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, indicating that combining NF-κB pathway and EGFR inhibitors may prove clinically useful.
- Trever G. Bivona
- , Haley Hieronymus
- & Charles L. Sawyers
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Letter |
DHODH modulates transcriptional elongation in the neural crest and melanoma
In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.
- Richard Mark White
- , Jennifer Cech
- & Leonard I. Zon
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News |
Female hormone could be key to male contraceptive
Progesterone-sensing molecule that guides sperm to egg offers fertility solution.
- Ewen Callaway
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News |
First lupus drug in half a century approved
A therapeutic antibody is the first success in a wave of experimental therapies aimed at tackling the autoimmune disease.
- Heidi Ledford
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Editorial |
Embrace change
US biomedical scientists should support bold plans to transform the process of drug development. Now is not the time for disunity.
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Letter |
The structural basis of agonist-induced activation in constitutively active rhodopsin
This study solves the X-ray crystal structure of a constitutively active mutant of rhodopsin, a G-protein-coupled receptor, bound to a peptide derived from the C-terminus of the G protein transducin. Comparison of this structure with the structure of ground-state rhodopsin suggests how translocation of the retinal β-ionone ring leads to a rotational tilt of transmembrane helix 6, the critical conformational change that occurs upon activation.
- Jörg Standfuss
- , Patricia C. Edwards
- & Gebhard F. X. Schertler
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News Q&A |
Deep future of drug discovery
For GlaxoSmithKline's research chief Patrick Vallance, drug development unites in-house depth with external breadth.
- Daniel Cressey
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News |
Traditional drug-discovery model ripe for reform
Academic researchers set to play much greater role in pharmaceutical development.
- Daniel Cressey
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Letter |
Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia
Substantial risk for schizophrenia is conferred by large copy number variants at a number of genomic loci. Here, a significant association between duplications on chromosome 7 and schizophrenia is reported. Importantly, microduplication analysis narrowed down the region to a region just upstream of a gene encoding vasoactive intestinal peptide receptor (VIPR2). Increased expression of VIPR2 in patients with schizophrenia implicates VIP signalling as a molecular mechanism underlying schizophrenia.
- Vladimir Vacic
- , Shane McCarthy
- & Jonathan Sebat
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News |
Genzyme deal set to alter biotech landscape
Maintaining innovative culture will be a key challenge for new owners of industry stalwart.
- Heidi Ledford
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News |
Licence rules hinder work on rare disease
Animal model off-limits to Rett-syndrome researchers.
- Erika Check Hayden
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News |
A new method of drug discovery
Public–private partnership proposed to develop pharmaceuticals.
- Daniel Cressey
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Comment |
Too many roads not taken
Most protein research focuses on those known before the human genome was mapped. Work on the slew discovered since, urge Aled M. Edwards and his colleagues.
- Aled M. Edwards
- , Ruth Isserlin
- & Frank H. Yu
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News & Views Forum |
A question of library design
Two approaches have emerged for creating libraries of compounds for use in biological screening assays for drug discovery — fragment-based ligand design and diversity-oriented synthesis. Advocates of each approach discuss their favoured strategy.
- Philip J. Hajduk
- , Warren R. J. D. Galloway
- & David R. Spring
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Review Article |
The challenge of new drug discovery for tuberculosis
- Anil Koul
- , Eric Arnoult
- & Koen Andries
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Spotlight |
Spotlight on Biotech/Pharma
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Research Highlights |
Promoter predicts drug results
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Letter |
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel
The mechanism of action of general anaesthetics is poorly understood, although there is some evidence that their principal protein targets are pentameric ligand-gated ion channels (pLGICs). Here, the X-ray crystal structures of propofol and desflurane bound to a bacterial homologue of the pLGIC family are solved. The structures reveal a common binding site for these two anaesthetics in the upper part of the transmembrane domain of each protomer.
- Hugues Nury
- , Catherine Van Renterghem
- & Pierre-Jean Corringer
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News |
Cells snag top modelling job
Heart disorder joins growing list of conditions getting the 'disease in a dish' treatment.
- Ewen Callaway
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News |
Near-action shots of vital proteins
Structures of G-protein-coupled receptors visualized in near-active states.
- Amy Maxmen
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Letter |
The structural basis for agonist and partial agonist action on a β1-adrenergic receptor
Here, the X-ray crystal structure of the β1 adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.
- Tony Warne
- , Rouslan Moukhametzianov
- & Christopher G. Tate
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Article |
Structure of a nanobody-stabilized active state of the β2 adrenoceptor
The X-ray crystal structure of the human β2 adrenergic receptor, a G-protein-coupled receptor, in an agonist-bound 'active' state is solved. Comparison of this structure with a previously published structure of the same GPCR in an inactive state indicates that minor changes in the binding pocket of the protein lead to major changes elsewhere — there is a large outward movement of the cytoplasmic end of one of the transmembrane segments and rearrangements of two other transmembrane segments. This structure provides insights into the process of agonist binding and activation.
- Søren G. F. Rasmussen
- , Hee-Jung Choi
- & Brian K. Kobilka
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News & Views |
Reader's block
Protein factors can regulate gene expression by binding to specifically modified DNA-associated proteins. Small molecules that selectively interfere with such interaction may be of therapeutic value. See Article p.1067 & Letter p.1119
- Sean D. Taverna
- & PhiliP A. Cole
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Outlook |
Interdisciplinary research: Big science at the table
Researchers are adopting the tools of bioinformatics and pharmaceuticals to study and interpret the ever-growing body of data on the interplay between diet and genes.
- Lucas Laursen
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Research Highlights |
Organic chemistry: Making maoecrystal V
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News |
Lack of support keeps African discoveries languishing in labs
Institutional frameworks must be improved to save stagnant technologies
- Linda Nordling
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Research Highlights |
Medicine: Profiling for blood pressure
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News |
Complex synthesis yields breast-cancer therapy
Drug approval marks culmination of a marathon trek from sea sponges to clinic.
- Heidi Ledford
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Editorial |
Treated fairly?
Moves to price new pharmaceuticals sensibly shouldn't damage the industry's health.
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Research Highlights |
Structural biology: Dopamine receptor revealed
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News |
Drug giants turn their backs on RNA interference
A once much-touted technique faces a difficult transition to the clinic.
- Heidi Ledford
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News |
Drugs to treat HIV found to prevent infection
Antiretroviral drugs shown to cut HIV transmission to men at high risk.
- Alla Katsnelson
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News |
Funding woes afflict African herbal therapy institute
Promising therapies in limbo after donor money runs out.
- Deborah-Fay Ndhlovu
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Letter |
Suppression of inflammation by a synthetic histone mimic
Post-translationally modified histones are recognized by effector proteins which contain specific binding modules; for example, the bromodomain-containing BET proteins bind acetylated lysine residues during gene activation. Here a synthetic small molecule is described that interferes with the binding of certain BET family members to acetylated histones. The compound inhibits activation of pro-inflammatory genes in macrophages and has activity in a mouse model of inflammatory disease.
- Edwige Nicodeme
- , Kate L. Jeffrey
- & Alexander Tarakhovsky
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News |
'Biosimilar' drugs poised to penetrate market
Draft regulations will pave the way for copycat antibodies and other large molecules.
- Heidi Ledford
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News |
UK drug-price overhaul set to shake up pharmaceutical industry
A bad value-based pricing system could threaten innovation.
- Daniel Cressey
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Letter |
Antibodies to human serum amyloid P component eliminate visceral amyloid deposits
Systemic amyloidosis is a serious disease caused by accumulation of amyloid fibrils in the viscera and connective tissues. Serum amyloid P component (SAP) is a normal plasma protein that concentrates within the amyloid deposits. These authors find that a combination of a drug that depletes circulating SAP and an antibody that targets residual SAP within the deposits results in clearance of amyloid deposits in a mouse model of the disease.
- Karl Bodin
- , Stephan Ellmerich
- & Mark B. Pepys
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News |
European research animal use holds steady
The use of transgenic mice is on the rise, along with non-animal alternatives.
- Alison Abbott
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Editorial |
Hope in translation
An increasing number of biomedical researchers are testing their ideas on people. The early-phase clinical-trial results are a promising sign of greater cooperation between scientists and clinicians.
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Article |
Selective inhibition of BET bromodomains
A new approach is used to target BET family bromodomains which are found in transcriptional regulators where they mediate the recognition of acetyl-lysine chromatin marks. Structural data reveal how the compound JQ1 binds to the bromodomain of BRD4. BRD4 has been implicated in a subtype of human squamous carcinomas, and JQ1 is found to inhibit the growth of BRD4 dependent tumours in mouse models.
- Panagis Filippakopoulos
- , Jun Qi
- & James E. Bradner
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News |
Rare victory in fight against melanoma
Genetically tailored approach could slow disease progress.
- Heidi Ledford
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Letter |
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF-mutant melanomas are highly dependent on B-RAF activity.
- Gideon Bollag
- , Peter Hirth
- & Keith Nolop
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Letter |
Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease
A major hallmark of Alzheimer's disease is the accumulation in the brain of amyloid-β peptide. This is generated by γ-secretase, which is thus of interest as a target for drugs to prevent amyloid-β accumulation. A problem is that γ-secretase has other substrates, including Notch, important in development. Here, a γ-secretase activating protein is identified that increases amyloid-β production without affecting Notch. Thus this protein can serve as an amyloid-β-lowering drug target without affecting other functions of γ-secretase.
- Gen He
- , Wenjie Luo
- & Paul Greengard
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News & Views |
Selectively tuning γ-secretase
Presenilin proteins have a major role in normal cellular processes, but some contribute to disease, for example through the formation of amyloid-β. The way in which these different roles are regulated is now becoming clearer.
- Peter St George-Hyslop
- & Gerold Schmitt-Ulms
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Correspondence |
Clarifying knowledge ownership in Europe's medicines initiative
- Kim De Rijck
- & Michel Goldman