Nature Reviews Drug Discovery 7, 1001 (2008). doi:10.1038/nrd2637

Author: Avi Ashkenazi

Each day, the human body eliminates billions of unwanted cells by apoptotic suicide. Apoptosis provides an important barrier against cancer; however, specific mutations enable some tumour cells to escape apoptotic death and become more malignant. Two signalling pathways initiate apoptosis: one acts through intracellular Bcl-2

Nature Reviews Drug Discovery 7, 975 (2008). doi:10.1038/nrd2771

Author: Monica Hoyos Flight

Jun N-terminal kinases (JNKs) phosphorylate and activate many cellular factors involved in disease processes, including diabetes, cancer, atherosclerosis and neurodegenerative diseases. As such, the potential of JNK inhibitors as therapeutics has attracted considerable interest. A key issue with kinase inhibitors, in particular with those that

Nature Reviews Drug Discovery 7, 978 (2008). doi:10.1038/nrd2772

Author: Man Tsuey Tse

A Phase II trial of tesofensine, an inhibitor of the presynaptic uptake of noradrenaline, dopamine and serotonin, suggests that it might induce double the weight loss in obese patients compared with currently used pharmacotherapies.Tesofensine was initially under investigation in Alzheimer's disease and Parkinson's disease

Nature Reviews Drug Discovery 7, 976 (2008). doi:10.1038/nrd2769

Author: Sarah Crunkhorn

T-cell-mediated autoimmune destruction of insulin-producing β cells of the pancreatic islets is pivotal in type 1 diabetes (DM1), but surprisingly few T-cell-directed therapies have proved successful in preclinical disease models. Unfortunately, islet transplantation does not represent a long-term solution owing to the gradual destruction of

Nature Reviews Drug Discovery 7, 979 (2008). doi:10.1038/nrd2656

Authors: Alexei Vazquez, Elisabeth E. Bond, Arnold J. Levine & Gareth L. Bond

The p53 pathway has been shown to mediate cellular stress responses; p53 can initiate DNA repair, cell-cycle arrest, senescence and, importantly, apoptosis. These responses have been implicated in an individual's ability to suppress tumour formation and to respond to many types of cancer therapy. Here

Nature Reviews Drug Discovery 7, 989 (2008). doi:10.1038/nrd2658

Authors: Guillaume Lessene, Peter E. Czabotar & Peter M. Colman

Overexpression of members of the BCL-2 family of pro-survival proteins is commonly associated with unfavourable pathogenesis in cancer. The convergence of cytotoxic stress signals on the extended BCL-2 protein family provides the biological rationale for directly targeting this family to induce apoptotic cell death. Recently,

Nature Reviews Drug Discovery 7, 971 (2008). doi:10.1038/nrd2662

Author: Shane Storey

Selective modulation of the apoptotic machinery has been the goal of oncology developers for more than two decades. The field continues to face special challenges. Many of the targets are intracellular protein–protein interactions, which are difficult to modulate. Developers are also addressing questions of how

Nature Reviews Drug Discovery 7, 1013 (2008). doi:10.1038/nrd2755

Authors: Inki Kim, Wenjie Xu & John C. Reed

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events,

Nature Reviews Drug Discovery 7, 959 (2008). doi:10.1038/nrd2756

Authors: Ernest C. Borden, Harriet Kluger & John Crowley

Dissection of the signalling pathways mediating apoptosis — controlled cell death — in cancer, inflammation and neurodegenerative disorders has stimulated the discovery of a wealth of potential drugs to target this process.

Nature Reviews Drug Discovery 7, 1031 (2008). doi:10.1038/nrd2759

Authors: Anwesha Dey, Vinay Tergaonkar & David P. Lane

The p53 and nuclear factor-κB (NF-κB) pathways play crucial roles in human cancer, in which inactivation of p53 and hyperactivation of NF-κB is a common occurrence. Activation of p53 and inhibition of NF-κB promotes apoptosis. Although drugs are being designed to selectively activate p53 or

Nature Reviews Drug Discovery 7, 957 (2008). doi:10.1038/nrd2763

Understanding of the molecular mechanisms of apoptosis and the role of its dysregulation in numerous diseases has advanced significantly in the past decade. This month, with the aim of highlighting the potential of harnessing such advances for therapeutic purposes, we present a special focus on

Nature Reviews Drug Discovery 7, 973 (2008). doi:10.1038/nrd2764

Authors: Emilio Perucca, Uma Yasothan, Gilbert Clincke & Peter Kirkpatrick

In August 2008, lacosamide (Vimpat; UCB), was granted market authorization by the European Commission as an adjunctive therapy for partial-onset seizures with or without secondary generalization in patients with epilepsy. It was approved by the FDA as an adjunctive therapy for partial-onset seizures in October

Nature Reviews Drug Discovery 7, 1041 (2008). doi:10.1038/nrd2765

As part of this month's special focus on apoptosis, two researchers in the field discuss their role in the development of therapeutic strategies to target apoptosis.

Nature Reviews Drug Discovery 7, 966 (2008). doi:10.1038/nrd2766

Non-Hodgkin's lymphoma. Biovest International has recently reported that data from a randomized, controlled Phase III trial show that the cancer vaccine BiovaxID significantly prolongs cancer-free survival for patients with follicular non-Hodgkin's lymphoma. The intent-to-treat analysis (n = 117) showed a median duration of

Nature Reviews Drug Discovery 7, 966 (2008). doi:10.1038/nrd2767

Shionogi and InterMune have announced the marketing approval of pirfenidone (Pirespa) for the treatment of idiopathic pulmonary fibrosis (IPF) in Japan, making it the first approved therapy for IPF in a major market. Shionogi developed pirfenidone in Japan and has rights in Japan, Taiwan and

Nature Reviews Drug Discovery 7, 967 (2008). doi:10.1038/nrd2768

Author: Michael Goodman

Using processed consensus investment research, AVOS Life Sciences has analysed the performance of the top 14 pharmaceutical companies as a group (see Supplementary information S1 (box)). The analysis focuses on each company's major Rx drug portfolio (MRDP; the collection of branded drugs each of

Nature Reviews Drug Discovery 7, 976 (2008). doi:10.1038/nrd2770

Author: Charlotte Harrison

Many G-protein-coupled receptors (GPCRs) possess two ligand binding sites: an orthosteric site to which endogenous ligands bind, and an allosteric site to which modulators can bind to alter the biological properties of the orthosteric ligand. However, most allosteric modulators lack signalling efficacy in their own

Nature Reviews Drug Discovery 7, 977 (2008). doi:10.1038/nrd2773

Author: Alexandra Flemming

The BCL-2 family, which is composed of pro- and anti-apoptotic proteins that regulate the mitochondrial pathway of programmed cell death, is a hotly pursued target for anticancer drugs. Most therapeutic approaches focus on inhibiting the function of the pro-survival protein BCL-2, thereby shifting the balance

Nature Reviews Drug Discovery 7, 978 (2008). doi:10.1038/nrd2774

Antibacterial drugsThe RNA polymerase “switch region” is a target for inhibitors.Mukhopadhyay, J.et al. Cell155, 295–307 (2008)The antibiotic myxopyronin inhibits bacterial RNA polymerase (RNAP). This paper shows that myxopyronin interacts with the RNAP

Nature Reviews Drug Discovery 7, 961 (2008). doi:10.1038/nrd2775

Author: Dan Jones

A wave of terminations of development programmes for cannabinoid receptor 1 blockers for obesity indicates the demise of a drug class that was once anticipated to yield blockbusters. Nevertheless, lessons learned might help salvage something for future such approaches.

Nature Reviews Drug Discovery 7, 963 (2008). doi:10.1038/nrd2776

The US FDA can now require companies to develop a risk evaluation and mitigation strategy (REMS) for therapeutic products. Bethan Hughes investigates the recent evolution of risk-management strategies in drug development.

Nature Reviews Drug Discovery 7, 964 (2008). doi:10.1038/nrd2777

JUPITER highlights anti-inflammatory effects of statin treatmentA large-scale trial shows that treatment with rosuvastatin (Crestor; AstraZeneca) reduces the incidence of major cardiovascular (CV) events in people without hyperlipidaemia who have high levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP).The lowdown: There

Nature Reviews Drug Discovery 7, 968 (2008). doi:10.1038/nrd2778

Author: Charlotte Harrison

What is a patentable process?In an eagerly awaited case, the US Court of Appeals has reached a decision on what constitutes a patentable process. US patents are granted for new and useful inventions relating to a machine, manufacture, composition (for example, drugs) or process.

Nature Reviews Drug Discovery 7, 970 (2008). doi:10.1038/nrd2779

The founder of PureTech Ventures discusses the firm's unique approach to company creation.