Reviews & Analysis

Interleukin 22 receptor 1 (IL-22R1) activity affects the development and course of disorders including psoriasis, ulcerative colitis, certain infections and tumours, without directly regulating immune cell function. Here, the authors describe the biology of IL-22 and highlight the therapeutic potential of modulating the activity of IL-22 and/or its receptor IL-22R1.

EPH receptor (EPH)–ephrin signalling has crucial roles in embryonic development, as well as in adult tissue and organ maintenance, regeneration and pathogenesis. Here, Lackmann and colleagues discuss the potential and limitations of targeting EPH–ephrin function in the treatment of disorders including cancer, neurological diseases and inflammation, and assess therapeutic approaches that are currently under development.

The Hippo signalling pathway is an emerging growth control pathway with roles in organ growth control, stem cell function, regeneration and tumour suppression. Here, Johnson and Halder review the regulation and functions of the Hippo signalling pathway, focusing on its potential to be therapeutically targeted in the treatment of cancer as well as tissue repair and regeneration following injury.

Cancer cells have high levels of reactive oxygen species (ROS) owing to metabolic and genetic alterations. The role of ROS in cancer cells is controversial as they can have both pro-tumorigenic and antitumorigenic properties. In this Review, Mak and colleagues discuss recent findings that cancer cells upregulate antioxidant pathways to counteract ROS, and explore the potential of anticancer strategies that target the antioxidant capacity of tumour cells.

The 'quality' of small-molecule drug candidates — encompassing aspects including their potency, selectivity and pharmacokinetic characteristics — is a key factor influencing the chances of success in clinical trials. Cumming and colleagues discuss the application of computational methods, particularly quantitative structure–activity relationships, in guiding the selection of higher-quality drug candidates, as well as cultural factors that may have affected their impact.

Regulatory agencies have been criticized both for being overly tolerant of risks or being excessively risk-averse, but the potential for adverse effects on public health owing to the absence of new drugs because of regulatory risk-aversion is less apparent. Here, Eichler and colleagues discuss the consequences of regulatory risk-aversion and suggest what might be done to best align acceptance of risk and uncertainty by regulators with the interests of public health.

Specific patterns of post-translational modifications in chromatin structure are important factors in the regulation of gene expression, and when deregulated they can contribute to diseases including cancer and neurological disorders. Here, Helin and colleagues focus on the role of one class of chromatin-modifier enzymes — the histone lysine demethylases — highlighting their links to cancer and their potential to be therapeutically targeted.

Non-coding RNAs (ncRNAs) are involved in the development of a number of diseases, including cancer, and the first ncRNA-targeted therapeutics have recently entered clinical trials. Here, Calin, Ling and Fabbri present the latest insights into ncRNA biology, with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and discuss how these inform therapeutic strategies that modulate ncRNAs in cancer.

Glycine transporters are important regulators of the level of glycine, which can act as both an inhibitory neurotransmitter and a modulator of neuronal excitation. Here, the authors discuss the potential of glycine transporters as novel therapeutic targets for schizophrenia, alcohol dependence and pain.

Cellular metabolism is substantially altered during oncogenesis and tumour progression, and targeting these metabolic changes is being actively pursued in the development of selective antineoplastic agents. Here, Kroemer and colleagues discuss the intimate relationship between metabolism and malignancy, focusing on therapeutic strategies and emerging agents targeting the metabolic rearrangements of cancer cells.

The development of drugs for autism spectrum disorder (ASD) is hampered by the limited understanding of its pathophysiology, the heterogeneity of its symptoms, a dearth of experimental models, and the lack of experience in clinical development. In this Review, Ghosh and colleagues present recent insights into the molecular underpinnings of ASD and how these have translated into new tools for drug development, and also new approaches to overcome the particular challenges in this field.

Bacteria that grow as aggregates in biofilms, in contrast to planktonic bacteria, are significantly more resistant to most antibiotics and microbicides. Chronic infections with such biofilms — for example, on implants, wounds and in the lungs of patients with cystic fibrosis — pose a serious medical problem. In this Review, Bjarnsholt and colleagues discuss the biological properties of biofilms and how these can inform the development of drugs that are active against biofilm infections.

Over the past decade, our understanding of the pathology of epilepsy and the causes of drug resistance has grown substantially, providing opportunities for the development of more effective anti-epileptic drugs (AEDs). Here, Löscher and colleagues discuss issues that may have hampered previous AED discovery and propose strategies for the development of improved epilepsy therapies that offer a compelling case for industry investment.

Here, the authors discuss issues relating to the co-development of targeted cancer therapies and companion diagnostics that were not covered in depth in the draft guidance released by the US Food and Drug Administration in 2011. They propose potential strategies that will be useful to mitigate challenges and to help guide the future co-development of drugs and diagnostics.

Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many diseases, including cancer, diabetes and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR). Hetz and colleagues discuss the opportunities to modulate components of UPR signalling to therapeutically manipulate levels of ER stress in disease.

Vast efforts have been made to develop novel anxiolytic drugs that improve on those that target the GABA (γ-aminobutyric acid)–benzodiazepine system, but promising results in rodents have rarely translated into effectiveness in humans. Griebel and Holmes analyse the major trends from a database of published preclinical studies on novel anxiolytic agents in the past 50 years, highlight issues that may have hampered progress and offer recommendations to improve anxiolytic drug discovery.

Sphingosine-1-phosphate (S1P) has a key role in the control of immune cell trafficking and is involved in disorders including cancer and inflammatory diseases. Here, Spiegel and colleagues discuss the ways in which S1P could be therapeutically targeted and highlight recent data from preclinical studies and clinical trials.

Members of the signal transducer and activator of transcription (STAT) protein family are implicated in a variety of diseases. In particular, aberrant activation of STAT3 is known to promote malignant transformation. In this Review, Turkson and colleagues discuss the various therapeutic approaches used to modulate the activation of the different STAT family members, which include dimerization inhibitors, tyrosine kinase inhibitors and DNA decoys.

Allosteric ligands bind to G protein-coupled receptors at a site distinct from the endogenous ligand. This Review discusses the potential advantages that allosteric ligands could hold, and highlights how the complexity of their actions provides both challenges and opportunities for drug screening.

Many clinical trial failures can be traced back to the limited predictive value of preclinical models of disease. Plenge and colleagues discuss how knowledge from human genetics, such as naturally occurring mutations in humans that affect the activity of particular proteins, can be used as a tool to more effectively prioritize molecular targets in drug development.