Reviews & Analysis

The efficacy–effectiveness gap describes the difference in drug performance under clinical trial conditions versus real-life conditions. Here, the authors argue that this phenomenon is due to variability in drug responses. They discuss the underlying biological and behavioural reasons for this phenomenon and propose strategies to 'bridge the gap'.

This Review highlights new therapeutic targets (for example, ventricular remodelling) and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between data from Phase II and Phase III trials.

Here, the authors highlight how inhibiting NOX1 and NOX2 oxidases could be a promising approach for combating oxidative stress. They discuss how a better understanding of the interactions of specific subunits of NADPH oxidases may enable the development of novel isoform-selective drugs to treat vascular diseases.

Treatment of type 1 diabetes by immunotherapy offers a novel strategy to improve clinical outcomes. Here, Waldron-Lynch and Herold discuss the immunopathogenesis of type 1 diabetes, the translation of experimental findings to clinical trials and future therapy.

Vessel normalization strategies aim to increase tumour perfusion and oxygenation, and have the potential to reduce metastasis and improve responses to conventional anticancer therapies. Here, Carmeliet and Jain discuss the benefits and limitations of this emerging new treatment paradigm for cancer and other angiogenic disorders.

Current atherosclerosis therapies largely act by lowering lipid levels and although they are effective, patients are still at risk for major adverse cardiovascular events (MACE). It has recently emerged that inflammation has a major role in the development of MACE and this is not addressed by existing agents. Here, Charo and Taub discuss key anti-inflammatory targets and associated therapeutics that are now being developed to treat atherosclerosis.

Synthetic lethality screening involves searching for genetic interactions of two mutations in which the presence of either mutation alone has no effect on cell viability, but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells could allow cancer cells to be selectively killed by mimicking the effect of the second of the two mutations with a targeted drug. Chan and Giaccia review strategies to identify synthetic lethal interactions and present case studies of anticancer agents that act by inducing synthetic lethality.

Regulation on orphan medicinal products was adopted in the European Union in 2000, with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. This article highlights the outcomes of this regulation, such as the approval of more than 60 orphan drugs, reflects on the experience gained so far and discusses key issues for the next 10 years.

Neuroprotective and/or disease-modifying treatments are urgently needed for Parkinson's disease. This Review describes how an increased understanding of genetic mutations that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improved design of future clinical trials are priorities for overcoming the limitations of current therapies.

Asymmetric dimethylarginine (ADMA), which is a product of post-translational methylation of arginine residues, inhibits nitric oxide synthases. This Review highlights the potential of modulating ADMA activity — by targeting the enzyme that metabolizes ADMA, dimethylarginine dimethylaminohydrolase — as a novel mechanism to regulate nitric oxide bioavailability in various pathologies, including sepsis.

Compounds that exhibit a covalent mechanism of action are typically avoided in drug discovery programmes, largely owing to safety concerns. Here, Singh and colleagues present the pharmacological advantages offered by covalent drugs and discuss strategies to address the potential risks and challenges that have been associated with these agents.

Chemically reactive metabolites (CRMs) can initiate serious adverse drug reactions. In their Review, Park and colleagues discuss current approaches for the evaluation of CRMs and examine how this knowledge can inform the various stages of the drug discovery and development process.

G-quadruplexes are four-stranded DNA structures that appear to be over-represented in the promoter region of various genes, including oncogenes such asMYC and KRAS. This article discusses evidence indicating the possibility of therapeutically modulating the transcription of such genes through the targeting of G-quadruplexes with small molecules, and considers challenges and opportunities for the development of such molecules as anticancer drugs.

Dysregulated cell death occurs in many human diseases, and modulating the associated pathways has proved effective in the treatment of cancer, stroke and neurodegenerative disorders. In their review, Kepp and colleagues provide an overview of assays capable of accurately quantifying distinct cell death pathways, focusing on those techniques that are applicable to high-throughput screening.

The reduction in attrition rates of cancer therapeutics in the clinic requires robust translational strategies. In their Perspective, Caponigro and Sellers review historical and current uses of preclinical model systems, and discuss how these systems can be optimized for rationally predicting the therapeutic benefit of drug candidates.

Brain-derived neurotrophic factor (BDNF), which acts through its receptor tropomyosin-related kinase receptor type B, has diverse effects on neuronal function and survival in the adult brain. Nagahara and Tuszynski review the potential therapeutic use of BDNF in the treatment of various disorders of the central nervous system, such as Alzheimer's disease, and discuss the challenges to effective delivery of BDNF and possible strategies to overcome them.

Has high-throughput screening (HTS) been unfairly blamed one factor responsible for the decline in productivity in the pharmaceutical industry? This article discusses some common misconceptions about the nature and value of HTS, and argues in support of its importance as a key tool in the discovery of novel chemotypes in drug discovery and chemical biology.

The Fc (crystallizable fragment) region of therapeutic antibodies can have an important role in their safety and efficacy. This article summarizes the current knowledge of antibody Fc functionality, provides a strategy for assessing the effector functions of different classes of therapeutic antibodies and proposes a path for routine testing and controls for manufacturers of antibody products.

Here, the authors examine the underlying mechanisms that result in cardiotoxicities of small molecule kinase inhibitors, highlight the challenges of making safe and selective kinase inhibitors and discuss how preclinical safety models might be used to predict clinical cardiotoxicity.

Activating mutations in Janus kinase 2 (JAK2) are a common feature of a number of myeloproliferative neoplasms. JAKs are also involved in the pathogenesis of inflammatory and immune-mediated disorders, and several JAK inhibitors are now in clinical development. In this Review, Quintás-Cardama and colleagues discuss the current progress in this field.