Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2014

Inflammation is now appreciated to have an important role in the pathogenesis of type 2 diabetes and associated complications. Donath describes the underlying mechanisms and discusses the rationale for the use of anti-inflammatory agents — such as those that have been developed for rheumatoid arthritis and other diseases driven by inflammatory processes — in patients with diabetes.

Evidence supporting the hypothesis that raising plasma levels of high-density lipoprotein (HDL) cholesterol could be cardioprotective has fuelled intense efforts to develop HDL-targeted therapies, but several recent clinical trial failures have introduced controversy. Kingwell and colleagues discuss the current understanding of the HDL hypothesis, considering what has been learned, what remains to be tested and how this knowledge could be used in the development of novel therapies.

The liver X receptors (LXRs) are key regulators of lipid homeostasis. Here, the authors highlight tissue-specific aspects of LXR function with a focus on the liver, intestine and brain, and discuss the implications of recent advances in the understanding of LXR activity for drug development.

The Notch signalling pathway, which is crucial for the development and homeostasis of most tissues, has been linked to a range of diseases, including cancer. Andersson and Lendahl discuss where and how to intervene therapeutically in the Notch signalling pathway, highlighting current achievements and remaining obstacles.

Inhibiting bromodomains — which are small interaction modules on proteins that assemble acetylation-dependent transcriptional regulatory complexes — could be a way to alter the expression of disease-promoting genes. Here, the authors highlight recent developments in the discovery of small-molecule bromodomain inhibitors and discuss how they might be used in cancer, inflammation and viral infection.

The cytokine interleukin-21 (IL-21) regulates immune responses and has potential therapeutic relevance in diseases including cancer, viral infections, autoimmune diseases and allergies. Spolski and Leonard describe our current understanding of IL-21 biology, and discuss progress in harnessing this knowledge therapeutically, including clinical trials of IL-21 itself and molecules that block IL-21 signalling.

Inhibitors of cyclic nucleotide phosphodiesterases (PDEs), which regulate concentrations of the key signalling intermediates cAMP and cGMP, are well established as drugs for disorders including erectile dysfunction and pulmonary hypertension. This article discusses how recent understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways is aiding the development of more sophisticated strategies to target individual PDE variants.

Aquaporin channels — which facilitate water transport across plasma membranes — are involved in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism. Here, the authors discuss the therapeutic potential of targeting aquaporin channels as well as associated challenges, such as the suitability of assay methods.

This Review highlights recent progress in the development of ligands to target two classes of nuclear receptors — the REV-ERBs and retinoic acid receptor-related orphan receptors (RORs) — and describes how such ligands might be useful for treating disorders related to metabolism, immune function and the circadian rhythm.

The tumour suppressor p53 is the most frequently mutated gene in human cancer, and drugs that restore or activate the p53 pathway have now reached clinical trials. Most of these drugs inhibit MDM2, a negative regulator of p53. In this Review, Lane and colleagues provide an overview of the different therapeutic approaches to targeting the p53 pathway and discuss the state of development of p53 pathway modulators.

Reduced number and function of insulin-secreting β-cells is a prominent feature of both type 1 and type 2 diabetes. Wagner and colleagues discuss strategies to promote β-cell proliferation, survival and function for the treatment of diabetes, and consider ongoing challenges to drug development efforts that are aimed at targeting this cell population.

Ligand efficiency metrics quantify the molecular properties required to gain binding affinity for a drug target. This article discusses the application of such metrics in the selection and optimization of fragments, hits and leads, highlighting how optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to increase the quality of drug candidates.

The activation of phosphoinositide 3-kinase (PI3K) signalling is nearly ubiquitous in human cancer, but inhibitors of this pathway have demonstrated only limited activity in the clinic. Here, Fruman and Rommel discuss the complexity of the PI3K signalling network in cancer, address challenges associated with therapeutic intervention and propose strategies to guide future efforts in translational and clinical research.

Herpesviruses can hijack the G protein-coupled receptor (GPCR)-mediated cellular signalling networks of their host, which subverts cellular signalling and contributes to viral pathogenesis. In this Review, the authors discuss how herpesvirus-encoded GPCRs could be promising targets in certain inflammatory and proliferative diseases.