Reviews & Analysis

The process of autophagy has recently sparked great interest as it is recognized to be involved in a wide range of diseases. The prospect of its manipulation for therapeutic purposes has led to the discovery of many exciting new potential drug targets.

The potential to use clinical biomarkers to better match therapies with specific patient populations — stratified medicine — is anticipated to have a major effect on both clinical practice and the development of new drugs and diagnostics. Trusheim, Berndt and Douglas discuss the implications of this approach to future product development strategies and market structures.

Biomarkers to diagnose neurodegenerative disorders early in their course and to monitor responses of patients to therapeutic interventions are urgently needed to optimize the development and application of novel disease-modifying drugs. Trojanowski and colleagues discuss progress and key issues in the discovery and validation of such biomarkers, with a focus on Alzheimer's disease.

Despite the clear need for better therapies for psychiatric disorders such as depression and schizophrenia, novel drugs — particularly those that could revolutionize treatment — have been rare in recent years. Following a symposium in which the underlying reasons for this problem were discussed, a group of experts from across the field of neuroscience highlight key advances in our understanding of psychiatric disorders, and propose steps that can be taken to improve the effectiveness of drug discovery in this field.

Lipophilic, poorly water-soluble drug candidates are common outcomes of drug discovery programmes. Porter and colleagues discuss mechanisms by which lipids and lipidic excipients can improve oral absorption of lipophilic drugs, and provide a perspective on the future applications of lipid-based delivery systems.

In this Review, Loging and colleagues discuss how high-throughput techniques in electronic biology can utilize the vast range of life sciencein silicoresources, and examine how best to apply these techniques to aid the drug discovery process.

The intrinsic robustness of biological systems is a key factor preventing the success of potential drugs that target specific molecules. Using examples based on existing drugs, Kitano discusses how a greater consideration of the importance of robustness could influence the design of new drugs intended to control complex systems.

Fragment-based drug design involves screening a small number of low-molecular-mass compounds with the aim of identifying low-affinity 'fragments' that are well-suited for optimization into more potent compounds. Hajduk and Greer describe the evolution of this approach into a valuable alternative to high-throughput screening for the discovery of lead compounds, and highlight lessons learned from its application over the past decade.

New therapeutic strategies are needed to improve the cure rate and quality of life in patients with acute lymphoblastic leukaemia. In this Review, Pui and Jeha discuss emerging new treatments that could improve the clinical outcome for these patients.

The therapeutic success of monoclonal antibodies has led to a steep rise in the use of non-human primates for preclinical safety testing. Chapman and colleagues report from a recent workshop on this topic, and discuss the economic, scientific and ethical questions raised by this development.

Being able to predict the individual effects of drugs on different patients in a population could lead to safer, more effective medicines. The authors discuss the development of algorithms that could enable the testing of drugs in virtual patient populations based onin vitrodata.

There is a major need for better therapies for many patients with heart failure, but late-stage clinical failures of several potential drugs have reduced the impetus of drug development in this field. Kaye and Krum review emerging agents and molecular targets for heart failure, and highlight key issues that need to be addressed to improve the chances of successfully developing new drugs.

The debate about whether truly novel, tractable targets exist for antibacterial drug discovery continues. Meanwhile, as Lynn Silver discusses, efforts are focused on learning from the 'good old targets' to improve current antibiotic classes and develop antibacterial strategies for the future.

The potential for using the lungs as a gateway for delivering drugs to the systemic circulation is attracting increasing attention. Here, Patton and Byron review current issues in the formulation and systemic delivery of small molecules and macromolecules as inhaled therapeutics.

Clinical use of biologic therapies for rheumatology has revealed that efficacy, toxicity and pharmacodynamic effects can deviate from those predicted. In this review, Issacs and colleagues summarize lessons gleaned from practical experience and discuss how these can inform future development of new biologic therapies.