Reviews & Analysis

A key issue in anticancer drug development is how best to select and evaluate potential combinations of the rapidly growing number of molecularly targeted drugs. Dancey and Chen consider development strategies for targeted-agent combinations, highlighting challenges for their rational preclinical and clinical evaluation, and discussing possible approaches to overcoming them.

Many phosphodiesterases are expressed in the CNS, and are attractive targets for the treatment of psychiatric and neurodegenerative disorders. Mennitiet al. review current understanding of the phosphodiesterase gene family in the CNS and the implications of targeting these enzymes in this therapeutic area.

Following the development of the first mTOR inhibitor that successfully improves therapeutic survival in cancer, Raymond and colleagues look at how novel biomarker identification and the use of multitargeted and multimodality therapies could advance the next generation of these drugs.

Mass spectrometry is emerging as a powerful analytical tool at various key stages in the drug discovery process. Hofstadler and Sannes-Lowery review the application of electrospray ionization mass spectrometry in the characterization of noncovalent complexes in drug discovery efforts against several classes of target.

The recent success of the B-cell-depleting antibody rituximab — originally developed as a lymphoma therapy — in the treatment of rheumatoid arthritis has stimulated considerable interest in the potential of drugs that can modulate B-cell function to treat autoimmune disorders. Browning discusses the role of B cells in a range of such disorders and analyses approaches to therapeutic B-cell manipulation.

The ubiquitin–proteasome pathway contains a large number of components that are possible drug targets for cancer and other diseases. Nalepaet al. review evidence linking components of this pathway to human disease and discuss potential strategies for therapeutic intervention.

Telomerase is expressed by cancer cells where it contributes to tumour maintenance, but is absent from most normal cells. Strategies for targeting telomerase therefore provide new opportunities for targeted cancer therapy. Shay and Wright review the current status and future opportunities for telomerase therapeutics.

Recent advances in our understanding of the signalling pathways activated in inflammation have revealed several potential therapeutic targets. O'Neill reviews these pathways and speculates on the likelihood of drugs being developed that will limit inflammation without a deleterious impact on host defence.

The discovery of Toll-like receptors (TLRs) offers the possibility to treat diseases by stimulating immune functions in a targeted manner. Krieg reviews the potential of synthetic DNAs that activate TLR9 and are in clinical development in cancer, infectious disease and asthma/allergy.

Target-oriented pharmacogenetic studies offer a unique opportunity to understand variations in response to highly selective protein therapeutics. Krejsa and colleagues review recent pharmacogenetic investigations of protein drugs, and present a case for initiating such studies during early clinical development.

Resveratrol is the constituent of red wine that has an array of protective effectsin vitro and in animal models. Baur and Sinclair provide a comprehensive review of the in vivoevidence that suggests resveratrol has therapeutic potential in humans.

The challenge of predicting potential efficacy of anti-atherosclerotic drugs before the completion of long-term trials with endpoints such as mortality has stimulated efforts to develop intermediate measures of efficacy. Nissen and colleagues describe how intravascular ultrasound can be applied to the serial assessment of atheroma burden in response to treatment, which has resulted in its emergence as a key technology in the evaluation and approval of novel drugs.

Gender-specific differences in cardiovascular diseases are likely to become more important in therapeutic decisions regarding cardiovascular drug design and development. Regitz-Zagrosek reviews gender-specific differences in the most frequent cardiovascular diseases, and discusses the implications of gender-specific effects of current cardiovascular drugs.

The simplicity and cost effectiveness ofC. eleganshas made it an attractive model organism for high-throughput screening and validation of genomics-derived targets. Kaletta and Hengartner review how this simple nematode can be used in various stages of drug discovery.

Morand and colleagues review the validation of macrophage migration inhibitory factor as a therapeutic target in atherosclerosis and rheumatoid arthritis, and explore how emerging small-molecule inhibitors could address a possible mechanistic link between these diseases.

fMRI is a relatively new technology that is now being evaluated for use in drug development. This has generated significant interest from biotech and pharmaceutical companies wishing to decrease the risk of drug development. Borsooket al. examine the potential use of fMRI as a tool to integrate drug development and optimize clinical development and later stage clinical trials.

The metabolic syndrome — a collection of factors associated with increased risk for cardiovascular disease and diabetes — is becoming increasingly common. Grundy summarizes the current understanding of the nature of the metabolic syndrome, and discusses each of the risk factors of the metabolic syndrome as possible drug targets.

The worldwide incidence of type 2 diabetes has reached epidemic proportions. More effective pharmaceutical options for the treatment of this devastating and costly disease are urgently needed. Dan Lazar and Alan Saltiel examine the exciting possibility that lipid phosphatases might provide a novel class of drug discovery targets for type 2 diabetes.

Advances in cellular imaging technology mean that we can now measure multiple cellular parameters at high resolution at subcellular, single-cell or cell-population level. Langet al. discuss the potential applications of this technology to drug R&D.

Multiplexed protein measurement is being established in applications such as comprehensive proteomic surveys, validation of genomic discoveries and clinical biomarker development. Kingsmore describes current and emerging multiplexed protein-measurement technologies and their applications, and discusses the challenges in this field.