Reviews & Analysis

Johnstone and colleagues discuss the molecular events that underlie the anticancer effects of histone deacetylase inhibitors, and consider how the clinical development and application of these agents may be optimized, either as monotherapies or in combination with other anticancer drugs.

Far from being simple degradative enzymes, proteases are now seen as key signalling molecules and desirable drug targets in several diseases. Turk discusses our success so far at targeting proteases and how these enzymes might be exploited therapeutically in the future.

The open-source software movement has successfully pioneered several strategies that might also be applicable in drug discovery and development. Munos considers the challenges involved, and proposes a model to harness the potential of open-source drug R&D.

The poor predictive ability of traditional xenograft mouse models is thought to be a key factor underlying failures of novel cancer drugs in clinical trials. Sharpless and DePinho describe the opportunities and challenges in the application of novel genetically engineered mouse models that more faithfully mimic human cancers, and their potential to improve the success of cancer drug development.

Pharmacological activity depends on the binding of drugs to their targets. Copelandet al. provide a perspective on the importance of residence time for lead optimization and describe the potential advantages of drugs with a long residence time, in terms of duration of pharmacological effects and selectivity.

Phosphodiesterase 5 inhibitors augment endogenous nitric oxide signalling, thereby restoring vascular reactivity to diseased blood vessels. Ghofrani and colleagues review the evolution of the PDE5 inhibitor sildenafil from a potential anti-angina drug, to an on-demand oral treatment for erectile dysfunction, and its recent re-positioning as a pulmonary hypertension therapeutic.

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.

Needle-free liquid jet injectors have been used for over five decades for delivery of numerous vaccines and drugs such as insulin, growth hormones and anaesthetics. Mitragotri reviews jet injectors with respect to their clinical and emerging applications, mechanistic understanding and future prospects.

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 reasons for the shortage of new drugs coming through the pipeline are the subject of much debate, and the pipeline for diagnostics is one factor that will become increasing relevant to this problem as the co-development of drugs and diagnostics becomes more common. Phillips and colleagues examine the characteristics of the pipeline for diagnostics and biomarkers, and consider what steps could be taken to solve the problems identified.

Advancement in personalized medicine depends on concurrent innovation in diagnostics and therapeutics. To remain competitive, drug discovery companies must embrace the powerful combination of genetic information in drug-responders and diagnostics that identify patient sub-groups.