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

Muscle atrophy can occur in patients with injuries or denervation of specific muscles, and muscle wasting occurs in patients with systemic diseases, including sepsis and cancer. This Review explains the pathophysiology of muscle wasting and discusses the progress of new therapies to treat this condition.

Mutations in components of the ERK pathway are a common occurrence in human cancer. Several drugs that target components of the ERK signalling cascade such as RAF, MEK and ERK have been approved or are in late-stage clinical development, and advances are being made in developing RAS inhibitors. Here, Samatar and Poulikakos discuss the particular challenges associated with each target and provide an overview of agents in development.

The goal of management for both type 1 and type 2 diabetes is the maintenance of blood glucose levels within healthy normoglycaemic ranges. However, safely achieving this goal using current therapeutic approaches has proved challenging. Here, Langer and colleagues review the developing role of nanotechnology in diabetes management, from diagnosis and disease monitoring to therapeutics.

Inhibition of E3 ubiquitin ligases, which provide substrate specificity to the ubiquitin proteasome system, is an attractive strategy to inhibit the degradation of a small subset of proteins. Skaaret al. discuss the progress that has been made in the development of therapeutic inhibitors of E3 ligases, in particular the SKP1–CUL1–F box protein (SCF) ubiquitin ligase complexes, and the challenges that lie ahead.

The failure of many clinical trials of the pioneering matrix metalloproteinase (MMP) inhibitors in oncology owing to lack of efficacy and side effects, such as musculoskeletal toxicity, reduced enthusiasm for further development of the drug class. Vandenbroucke and Libert discuss how greater knowledge of MMP biology, as well as the development of more specific MMP inhibitors, could provide new opportunities to use such agents in the treatment of sepsis and other inflammatory disorders.

Hypoxia-inducible factors (HIFs) have important roles in ischaemic and inflammatory diseases and strategies aimed at therapeutically modulating hypoxia signalling pathways are gaining considerable attention. Here, Eltzschig and colleagues focus on a set of oxygen-sensing prolyl hydroxylases — which are responsible for marking HIFs for proteasomal degradation — and assess their emerging potential as therapeutic targets.

Although previous attempts to therapeutically target RAS proteins — which are frequently mutationally activated in cancer — have been unsuccessful, recent advances in our understanding of these signalling proteins have led to a renewed interest in RAS-targeted therapies. Der and colleagues discuss progress with a range of established and emerging strategies to interfere with RAS function, and highlight the most promising avenues for future anticancer drug discovery efforts.

Multifunctional and stimulus-sensitive nanoparticles can overcome issues associated with traditional drug delivery by, for example, improving targeting and bioavailability. Here, Torchilin highlights recent developments in these types of nanocarriers and how they can also include imaging contrast moieties to track their real-time biodistribution and accumulation at the target site.

The therapeutic potential ofin vitro-transcribed mRNA (IVT mRNA) extends from prophylactic and therapeutic vaccines to applications such as protein replacement and genome engineering. In this Review, the authors describe the recent developments in the IVT mRNA field, discuss the class-specific challenges with regards to translating IVT mRNA into a biopharmaceutical, and provide an overview of IVT mRNA drugs in development for different indications.

Sepsis is a potentially fatal systemic disease that is caused by microbial infection. Despite numerous clinical trials, no specific therapeutic agent has yet been approved for this indication. Here, Fink and Warren consider potential reasons for such failures and suggest possible strategies to overcome ongoing challenges, such as improving clinical trial design.

G protein-coupled receptors (GPCRs) are highly successful drug targets, particularly for central nervous system (CNS) disorders. Compared to traditional drugs that target the orthosteric ligand-binding site of GPCRs, allosteric modulators have the potential to achieve greater subtype selectivity and allow the normal function of endogenous ligands to be preserved. Conn and colleagues reflect on the key principles for successful optimization of GPCR allosteric modulators.

Histone deacetylases (HDACs) are a class of epigenetic enzymes that remove acetyl groups from lysine residues on histones and other proteins. In this Review, the authors highlight the role of HDACs in cancer, neurological diseases and immune disorders, and discuss the development of small-molecule inhibitors.

Biological drugs offer high specificity and potency, but their formulation and delivery pose substantial challenges. Here, the authors highlight recent advances in formulation strategies, describe current and emerging delivery routes and review the potential of targeted and intracellular delivery of biologics.

Semaphorins — a group of cell-surface and secreted proteins whose effects are mediated by plexin receptors — are involved in intercellular communication in the nervous system, the immune system and during angiogenesis. Worzfeld and Offermanns summarize the pathological roles of semaphorins and plexins in cancer, bone diseases, immuno-inflammatory diseases and spinal cord injury, and discuss emerging strategies to therapeutically target these molecules.

Previous analyses of new drug approvals have suggested that phenotypic screening strategies have been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. Eder and colleagues analysed the origins of the first-in-class drugs approved by the US Food and Drug Administration from 1999 to 2013, and found that target-based approaches have had a substantial impact in more recent years. They discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Moffat and colleagues investigated the contribution of phenotypic assays in oncology by analysing the origins of the new small-molecule cancer drugs approved by the US Food and Drug Administration over the past 15 years. They also discuss technical and biological advances that could empower phenotypic drug discovery in oncology by enabling the development of mechanistically informed phenotypic screens.

MicroRNAs (miRNAs) — 21- to 23-nucleotide single-stranded RNAs that regulate gene expression — have roles in numerous diseases, and are therefore attractive therapeutic targets. Li and Rana discuss strategies in the design of miRNA-targeting oligonucleotides with increased efficacy and improvedin vivodelivery characteristics, and highlight some of the challenges that lie ahead in the clinical development of these therapeutics.

The WNT pathway has a vast array of functions and aberrant WNT signalling is correspondingly implicated in numerous diseases, including cancer, fibrosis and nervous system disorders. Kahn discusses our understanding of this developmentally important pathway, the complexities associated with safely targeting it therapeutically and WNT-modulating agents that are currently being investigated.

Here, the authors highlight how neuroinflammation in the nervous system is a key driver of chronic pain, and how targeting the key molecules involved in neuroinflammation may offer new therapeutic options for hard-to-treat pain.

Over the past few years, considerable progress has been made in understanding the biology, pharmacology and structure of muscarinic acetylcholine receptors (mAChRs). Here, Wess and colleagues discuss the therapeutic potential of targeting this class of receptors in a range of diseases, including Alzheimer's disease and type 2 diabetes, and consider novel aspects of mAChR pharmacology that could enable modulation of specific receptor subtypes.