Review Articles in 2010

Many G protein-coupled receptors (GPCRs) are involved in the initiation and/or progression of cancer. Here, the authors discuss recent advances regarding the involvement of GPCRs in cancer and address the implications of these findings towards the discovery of innovative drug targets for cancer prevention and treatment.

The anticoagulant rivaroxaban is the first approved direct inhibitor of the serine protease factor Xa. This article presents the history of rivaroxaban's development, from its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.

The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis, and their functional importance in various diseases, including cancer, cardiovascular disease and neurodegenerative disorders, is now beginning to emerge. Brownell and colleagues review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention.

The expression of TSPO, a mitochondrial translocator protein involved in steroid synthesis, in the nervous system is altered in numerous neurological and psychiatric conditions. Rupprecht and colleagues review the potential of TSPO ligands for the treatment and diagnosis of disorders including anxiety, neuropathic pain and amyotrophic lateral sclerosis.

Here, the authors discuss the potential of tyrosine kinase inhibitors — currently used for the treatment of cancer — as anti-proliferative agents in non-malignant disorders such as cardiac hypertrophy, pulmonary hypertension, lung fibrosis and rheumatoid disorders.

The vitamin D endocrine system is a well-established target for metabolic bone disorders. Furthermore, the identification of the vitamin D receptor in tissues not related to calcium and bone has stimulated interest in its therapeutic significance in autoimmune diseases, cardiovascular disorders, infectious diseases and cancer. Plum and DeLuca highlight the emerging opportunities for vitamin D-based therapies in those diseases for which the evidence of their potential is most compelling.

In September 2010, fingolimod (FTY720/Gilenya; Novartis) became the first oral disease-modifying therapy to be approved by the US Food and Drug Administration for relapsing–remitting multiple sclerosis. Brinkmann and colleagues describe its discovery and development, and how elucidation of its effects on sphingosine 1-phosphate receptors has improved the understanding of the biology of these receptors.

MicroRNAs (miRNAs) are attracting increasing attention as promising targets for the treatment of cancer. Here, the authors discuss the role of miRNAs in cancer development, and discuss the rationale, the strategies and the challenges for developing therapeutics that modulate miRNAs.

Integrins — a large family of cell adhesion molecules — have been extensively investigated as targets for diseases including thrombosis, cancer and autoimmune disorders. This article discusses how recent advances in understanding of integrin structure, function, ligand interaction and signalling pathways, as well as lessons learned from first-generation integrin antagonists, are indicating novel strategies for inhibiting integrins that could help exploit their full therapeutic potential.

Compounds that alter microtubule function can be highly active in patients with cancer. Here, the authors review the mechanisms of action of and resistance to microtubule-binding agents, then highlight novel anticancer microtubule-binding agents that have recently been approved or reached clinical trials.

Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule. Here, the authors review the physiology of CO, summarize the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discuss the therapeutic development of this gaseous molecule.

Cytokines — key instigators and regulators of immune responses — hold potential as targets for new therapeutic strategies. Here, Kopf and colleagues highlight some of the most effective and promising cytokine targets that have been linked to inflammatory diseases in preclinical and clinical studies and discuss some of the issues facing the development of cytokine-targeted drugs.

The incidence of invasive fungal infections is increasing, and there is an unmet need for new antifungal drugs. This article provides an overview of the history of antifungal drug discovery, discusses the current pipeline and presents new vaccination and immunotherapeutic approaches to treat fungal infections.

Polo-like kinase 1 (PLK1), which helps orchestrate key events in the cell cycle, has been preclinically validated as an anticancer target, whereas it seems that the closely related kinases PLK2 and PLK3 might act as tumour suppressors. Strebhardt reviews recent insights into the biology of PLKs, with emphasis on their role in malignant transformation, and examines progress in the development of small-molecule PLK1 inhibitors as anticancer drugs.

Advances in nanoparticle engineering, and in understanding of the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications such as targeted drug delivery. Petros and DeSimone review the impact of nanoparticle characteristics on their biological properties and recent progress in the rational design of nanoparticle therapeutics, discussing the challenges to realizing their potential.

Advances in therapeutic strategies for Alzheimer's disease depend on the identification and qualification of biomarkers. Here, the authors review the current status of candidate biomarkers for Alzheimer's disease and provide the perspectives of different stakeholders on biomarker discovery and development.

Aptamers are oligonucleotide sequences that are capable of recognizing target proteins with an affinity and specificity rivalling that of antibodies. In this article, Keefe and colleagues discuss the development, properties and therapeutic potential of aptamers, highlighting those currently in the clinic.

All available antidepressants act through monoaminergic mechanisms, and there is considerable interest in novel approaches that might improve treatment. One such strategy focuses on melatonin, a key regulator of circadian rhythms, which are perturbed in depression. This article describes the history of agomelatine, which possesses both melatonergic agonist and 5-hydroxytryptamine 2C antagonist properties. It was granted marketing authorization in Europe in 2009, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

Most current obesity therapies aim to reduce calorific intake or absorption and are limited by poor efficacy or unpleasant side effects. Here, Tseng and colleagues discuss the therapeutic potential of the alternative approach of increasing cellular energy expenditure, principally by stimulating adaptive thermogenesis, to prevent or treat this disorder.

Preventing the reabsorption of glucose in the kidney by inhibiting the sodium–glucose co-transporters (SGLTs) is emerging as a promising new strategy to treat type 2 diabetes. Here, Chao and Henry give an overview of the role of the kidney in glucose homeostasis and discuss the development and potential of SGLT2-selective inhibitors, reviewing those agents currently undergoing clinical investigation.