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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.
Chorus is a small, operationally independent organization within Eli Lilly and Company that specializes in drug development from candidate selection through to clinical proof of concept. Here, we describe its development philosophy, organizational structure, operational model and results in the decade since it was established, which indicate substantial productivity improvements in both time and cost compared to traditional drug development approaches.
Potential drug–drug interactions mediated by ATP-binding cassette (ABC) and solute carrier (SLC) transporters are of clinical and regulatory concern, but the endogenous function of these drug transporters is unclear. Nigam describes the evidence that these transporters transport diverse endogenous substrates and could potentially be important in remote communication. Understanding such functions could clarify the roles of these transporters in disease and in drug–metabolite interactions.
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.
Caloric restriction can promote health and extend the lifespan of model organisms, and diverse classes of compounds that mimic the biochemical and functional effects of caloric restriction have attracted considerable interest as potential pharmacotherapies for diseases such as diabetes and obesity. Kroemer, Madeo and colleagues propose a unifying definition of caloric restriction mimetics as agents that induce autophagy by promoting protein deacetylation, which could have implications for their development as drugs.
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.
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.
Over the past decade, cancer stem cells have emerged as the centerpiece of cancer research, having a major role in resistance to conventional therapy and in the metastatic spread of tumours. The authors discuss the biological complexity of this subpopulation of cells within tumours and explore novel means to tackle them therapeutically based on our current understanding.
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.