Reviews & Analysis

Cell surface carbohydrates and carbohydrate-binding proteins mediate many key recognition events. This article reviews current progress in the development of glycomimetics and the opportunities and challenges presented by this relatively untapped source of therapeutics.

The focus for the use of bioinformatics resources in the pharmaceutical industry is increasingly moving from the vigorous pursuit of intellectual property towards exploration of pre-competitive collaborations and engagement with the public domain. In this article, we discuss the rationale for these changes and the associated challenges, and also propose new areas of public–private collaboration in computational biology and chemistry that could enhance drug discovery in academia and industry.

Here, Kenakin discusses how the efficacy of drugs that act at seven-transmembrane receptors is linked to the particular pharmacological assay used to observe the effects of the drug, and highlights how a return to whole–system assays is adding value to the drug discovery process.

Aberrant activity of cell cycle protein kinases, leading to uncontrolled cell proliferation, is a hallmark of human cancer. Here, Lapenna and Giordano review recent progress in the modulation of specific protein kinase activity for the treatment of various cancers and identify novel strategies for the design of new agents.

Here, the authors summarize the current state of multi-parameter profiling technologies and how phenotypic profiling of small molecules provides important insights into their mechanisms of action, as well as a systems level understanding of biological pathways and their responses to drug treatments.

More effective prediction of 'translational success' could have a key role in addressing the widely acknowledged problems with weak drug development pipelines. This article discusses how establishing a scoring system to systematically assess key determinants of translational success, such as biomarkers and animal and human data, could help achieve this goal.

In this Review, the authors emphasize a translational approach to pharmacotherapy development for the treatment of drug addiction, whereby existing medications are used to validate and improve animal and human laboratory models to identify potential new therapies.

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular sensors that have key roles in innate immunity and inflammation. This Review discusses the effect that research on NLRs will have on vaccination, treatment of chronic inflammatory disorders and acute bacterial infections.

A chronic inflammatory state, leading to local and systemic deleterious effects on host cells and tissues, is maintained in several diseases. Here, Gaestel and colleagues review current understanding of the roles and molecular mechanisms of kinase signalling in inflammation, emphasizing the most recent advances in the development of specific small-molecule kinase inhibitors for the treatment of chronic inflammation.

Drug resistance and the genomic instability of cancer cells hamper current gene-targeting therapeutic strategies for cancer. As Huang and colleagues discuss, targeting the unique biochemical properties of cancer cells — in particular, increased oxidative stress — might represent an alternative approach for the development of selective, redox-modulating anticancer agents.

Long-term diabetes increases the likelihood of developing complications such as macrovascular disease, nephropathy, retinopathy and neuropathy. This Review highlights the range of pathologies that are precipitated by hyperglycaemia and discusses recent developments in preclinical and clinical research for each of these complications.

Cardiovascular disease associated with type 2 diabetes has become a major issue in the development of new diabetes therapies. DeSouza and Fonseca review the background to and implications of recent regulatory guidance for cardiovascular risk assessment of new antidiabetic agents, and discuss the potential beneficial cardiovascular effects of selected agents currently in development.

The growing appreciation of the regulatory role of the central nervous system (CNS) in energy and glucose homeostasis has the potential to lead to more effective long–term treatments for obesity and type 2 diabetes. Here, Sandoval and colleagues discuss the CNS pathways involved, identify promising therapeutic targets and strategies for diabetes and consider the associated challenges hampering the development of new agents.

The glucose-phosphorylating enzyme glucokinase acts as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and also regulates hepatic glucose production, and is therefore a potential therapeutic target for the treatment of type 2 diabetes. Here, Matschinsky discusses the physiological roles of glucokinase and the most recent progress in the development of pharmacological glucokinase activators.

Therapies based on the incretin hormone glucagon-like peptide 1 (GLP1) have proved to be successful in the treatment of type 2 diabetes. In this article, Ahrén reviews recent progress in the development of improved GLP1 modulators and discusses the therapeutic potential of other islet β-cell G protein-coupled receptors that are involved in the regulation of islet function, including GPR40 and GPR119.

Large-scale generation and integration of genomic, proteomic and metabolomic data are increasingly allowing the construction of complex networks that provide a new framework for understanding the molecular basis of disease states. This Opinion article highlights how this knowledge could be applied to network-based drug discovery to investigate the impact of interventions — such as candidate drugs — on the molecular networks that define these states, and could ultimately be used to develop improved therapies.

Thyroid hormone excess has potentially useful effects, including lowering of serum cholesterol and reduction of body fat. However, the therapeutic application of this hormone has so far been hampered by deleterious effects on the heart, muscle and bone. This article reviews recent progress in the development of selective thyroid hormone mimetics that seem to lack the adverse actions associated with thyroid hormone itself, making them a promising new strategy for the treatment of atherosclerosis, obesity and type 2 diabetes.

Scholich and colleagues highlight how an increased knowledge of the physiological functions of different mammalian adenylyl cyclases, combined with advances in the development of isoform-selective adenylyl cyclase modulators indicates that these enzymes could be useful drug targets.

The regulation of endothelia is vital for the maintenance of homeostasis, and their disruption is observed in many disease states. Sphingosine-1-phosphate (S1P) receptors have emerged as reversible modulators of endothelial barriers, which could lead to the development of highly specific, barrier-oriented small-molecule-based therapeutics for treating conditions ranging from multiple sclerosis to acute respiratory distress syndrome.

Although the potential of 'personalized medicine' to increase the quality of clinical care and decrease health-care costs has been recognized for many years, only a handful of associated diagnostic tests have made it to market so far, with mixed success. This article proposes that the major challenges to the further adoption of personalized medicine are increasingly related to economics, and discusses strategies that could help address these challenges.