Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2012

Effectively selecting therapeutic targets from the sizeable lists that are emerging from large-scale multi-omics initiatives is a key challenge in drug discovery. This article describes an objective, systematic computational assessment of biological and chemical space that can be applied to any human gene set to prioritize targets for further evaluation, and demonstrates its use on a set of 479 cancer-associated genes to identify new opportunities for drug discovery and repurposing.

Regulatory T (T_Reg) cells are essential mediators of immune homeostasis. They are attractive targets for steering the immune system in desired directions — arming it to destroy cancer cells or downregulating it in autoimmunity. In this Review, Daniel and von Boehmer discuss how molecular insights into the generation and proliferation of these cells can be exploited for new therapeutic approaches.

Most metabolites of the kynurenine pathway — which metabolizes tryptophan — are neuroactive. This Review describes the role of the kynurenine pathway in the pathology of Huntington's disease, migraine and multiple sclerosis, and highlights the most promising compounds that could be of therapeutic value.

Tankyrases — members of the poly(ADP-ribose) polymerase (PARP) protein superfamily — are involved in diverse cellular processes, including WNT signalling and telomere maintenance. Here, the authors describe the biology of tankyrases and the discovery of tankyrase-specific inhibitors, which could have broad clinical utility. The challenges that lie ahead for the clinical development of PARP family inhibitors in general are also examined.

Here, the authors discuss how cytokines could be used as therapeutic targets for individuals with asthma that is inadequately controlled using current therapies. They also highlight the need for phenotyping asthma subtypes in order to achieve the best possible patient-focused treatment.

The protein kinase C (PKC) family of highly related protein kinases are implicated in several diseases and have been a major focus of drug discovery efforts. However, no single drug specifically targeting a PKC isozyme has yet received approval. Here, Mochly-Rosen and colleagues review the efforts, challenges and opportunities in developing PKC modulators.

A number of compounds, derived from bacterial fermentation products, have been found to target subunits of the spliceosome and display anticancer properties. In this Review, Valcárcel and colleagues discuss the role of splicing in cancer and how insights into the mechanism of action of these bacterial compounds might lead to the development of novel antitumour drugs.

MicroRNAs (miRNAs) are involved in the regulation of gene expression and have been implicated in the pathology of several diseases. Here, van Rooij and Olson discuss the chemistry of current miRNA inhibitors and evaluate miRNAs as potential therapeutic targets for cardiovascular disorders.

Vemurafenib is a small-molecule inhibitor of the oncogenic BRAF kinase approved for the treatment of melanoma. Here, the scientists involved in the discovery of vemurafenib describe the underlying biology of BRAF, the technology used to identify vemurafenib and its clinical development milestones, along with future prospects based on lessons learned during its development.

This Review highlights the role of T helper 17 (T_H17) cells and interleukin-17 (IL-17) in the pathogenesis of inflammatory diseases, and discusses key advances and challenges in targeting IL-17 in disorders such as psoriasis, rheumatoid arthritis and ankylosing spondylitis.

Bacterial degradative proteases are essential for growth and survival, representing attractive targets for the development of novel antibacterials. However, despite pharmaceutical successes with protease modulators in several diseases, this class of enzymes has not yet been targeted to treat bacterial infections. Here, Rubin and colleagues review the biological roles of key prokaryotic degradative proteases, highlighting recent advances and challenges in their therapeutic exploitation.

The transforming growth factor-β (TGFβ) signalling pathway is implicated in a variety of disorders, including cancer, fibrosis and inflammation, and has become an attractive target for drug development. Here, Akhurst and Hata present therapeutic strategies for intervening in this pathway and discuss agents currently under investigation while addressing the associated challenges in their development and application.

The lysosomal degradation pathway known as autophagy has an essential homeostatic role in controlling the quality of the cytoplasm. However, this pathway has also been implicated in the pathology of an array of human disorders. Here, Rubinsztein and colleagues provide an overview of the mechanisms and regulation of autophagy, discuss the role of this pathway in disease and highlight potential strategies for therapeutic modulation.

Disappointing clinical trials halted progress in using leptin for the treatment of obesity. Here, the authors propose a role for leptin in the treatment of type 1 diabetes and postulate that if the mechanisms of leptin resistance are better understood, leptin may become an important adjunct tool for the treatment of type 2 diabetes.

Effective and safe pharmacological options for the prevention and treatment of obesity remain elusive. Here, Dietrich and Horvath review the role of the hypothalamus in the control of food intake and the mechanism of action of current anti-obesity agents. They propose that targeting hunger pathways, such as those activated during calorie restriction and exercise, might lead to safer long-term obesity therapies.

Blockade of the pro-inflammatory cytokine interleukin-1 (IL-1) is emerging as an effective approach for the treatment of an increasing number of diseases. Here, Dinarello and colleagues discuss the pathogenic roles of IL-1, present therapeutic strategies aimed at modulating the activity of this cytokine and review clinical trial data for multiple indications.

Manz and colleagues discuss recent progress in the development of microfluidic techniques (lab-on-a-chip technology) and their applications in drug discovery. Highlights include high-throughput droplet technology and applications such as 'organs on a chip', which could help reduce reliance on animal testing.

A growing number of G protein-coupled receptors (GPCRs) are being identified as sensors for ligands that are energy substrates or metabolic intermediates, and their central role in the coordination of metabolic processes is increasingly being recognized. Offermanns and colleagues summarize the function of these metabolite-sensing GPCRs in physiology and disease, and discuss the emerging pharmacological agents that are being developed to target these GPCRs for the treatment of metabolic disorders.

Biopharmaceuticals are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions (also known as biosimilars). Jones and colleagues discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation.

The paucity of treatments for schizophrenia might be partly due to the lack of suitable animal models in which to assess potential new drugs. Here, the authors highlight how new rodent models that are based on a better understanding of the genetics and neural circuitry underlying schizophrenia could lead to the development of more effective drugs.