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Isothermal titration calorimetry can be used to obtain thermodynamic data on the binding of compounds to protein targets. Ladbury and colleagues propose that these data — particularly the change in enthalpy — could be a valuable addition to established tools for selecting compounds in lead discovery and for aiding lead optimization.
The complement system has long been known to have a pathogenic role in various disorders, but the therapeutic potential of modulating complement responses has only recently been recognized. In this article, Wagner and Frank review those diseases associated with complement activation and deregulation and focus on promising therapeutic strategies and agents that are currently in the clinic.
Voltage-gated K+ channels (KV) are involved in diverse physiological processes and offer important drug development opportunities for cancer and autoimmune diseases, as well as metabolic, neurological and cardiovascular disorders. Here, Wulff and colleagues discuss strategies to pharmacologically modulate KV channels and highlight recent progress in developing drugs that target specific KVsubfamilies.
Proteomics techniques can be applied in drug target identification and validation, but data interpretation can be complicated by the identification of proteins in unexpected cellular locations. Here, Butler and Overall discuss the importance of recognizing that many intracellular proteins may have physiological functions in the extracellular compartment, and its implications for drug discovery.
The emerging resistance to current antimalarial drugs calls for new strategies to control the disease. This article highlights the potential of targeting the obligate short-lived hepatic forms of the malaria parasite and ways to overcome the challenges of developing drugs that will achieve this.
Although protein kinases are proving to be valuable therapeutic targets for various peripheral-tissue disorders, the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge. Here, Chico and colleagues discuss the issues associated with CNS drug discovery, present trends in small-molecule properties associated with blood–brain barrier penetrance and review emerging CNS protein kinase targets and compounds in development.
Many inhibitors of histone deacetylases (HDACs) are in trials in patients with cancer, but a subset of HDAC inhibitors also have anti-inflammatory or immunosuppressive effects that may be of therapeutic benefit in autoimmune diseases or post-transplantation. Hancock and colleagues describe these effects, highlighting the importance of the ability of some HDAC inhibitors to enhance the production and suppressive functions of FOXP3+regulatory T cells, and discuss the potential to develop class- or subclass-specific HDAC inhibitors as novel immunotherapies.
The recent call for the eradication of malaria has sparked the development of new drug classes with improved product profiles. Wells and colleagues review the currently available antimalarials and their limitations, the contribution of genome-based technologies andin vitroscreening of whole parasites to the discovery of new targets, and the issues that should be considered when developing such antimalarials.
Orloff and colleagues describe how moving from the traditional approach to clinical trials based on sequential, distinct phases towards a more integrated strategy that increases flexibility and maximizes the use of accumulated knowledge could have a key role in improving the efficiency and cost-effectiveness of drug development. Using examples in which novel trial designs have been successfully applied, they also illustrate the use of the tools involved, such as Bayesian methodologies, and discuss the advantages and challenges for their more widespread implementation.
Misfolded tau is found in a number of neurodegenerative diseases, including Alzheimer's disease, and could lead to neuronal dysfunction, owing to the formation of toxic species or loss of normal tau function. Given the recent failures of amyloid-β-targeted therapies, the tau-directed drug discovery programmes reviewed here could be an alternative strategy for the treatment of Alzheimer's disease.
Inhibition of the soluble epoxide hydrolase (sEH) enzyme diminishes degradation of epoxyeicosatrienoic acids, which can enhance their beneficial cardiovascular actions. Here, Imig and Hammock highlight the rapid development of sEH inhibitors, and discuss their potential as a therapy for cardiovascular diseases.
The hypothesis that cancer is driven by tumour-initiating cells — popularly known as cancer stem cells — has recently attracted considerable attention, owing to the promise of a novel cellular target for the treatment of haematopoietic and solid malignancies. This Review considers recent advances in the cancer stem cell field, focusing on the challenges and opportunities for anticancer drug discovery.
The need to manage drug safety issues is an increasingly common feature of drug research, regulation and prescription. This article discusses several key areas for development that could deliver long-term solutions to drug safety challenges: enhanced tools for the detection of safety signals, innovative phased drug launches, new risk stratification techniques and improved pharmacovigilance operations.
The importance of pharmacovigilance — the ongoing assessment of the safety of a marketed medicine — has been increasingly appreciated in recent years. Breckenridge and colleagues summarize the key tools that are available for pharmacovigilance, discuss which might be the most appropriate to use in different situations and consider the future directions of the field.
The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, the activity of which modulates many neurotransmitter systems. They are therefore therapeutic targets for the treatment of several central nervous system disorders. In this article, Taly and colleagues present recent advances in our understanding of the atomic structure, functional organization and conformational transitions of the nAChR that may be applied to drug discovery, and discuss agents currently in development.
The protein methyltransferases (PMTs) are emerging as a group of enzymes that play key parts in human diseases. This Review highlights data that support the validation of PMTs as therapeutic targets, including the structural and mechanistic data that support the concept of the PMTs as a druggable target class.
Drug repurposing, in which an established active pharmaceutical ingredient is applied in a new way — for example, in a new presentation, often combined with a new therapeutic indication — is an evolving strategy for pharmaceutical R&D. This article discusses each aspect of this strategy, highlighting commercial successes that have arisen from a focus on the presentation and therapeutic use of known active ingredients or slight variations of these compounds.
The phosphoinositide 3-kinase (PI3K) signal transduction pathway is often inappropriately activated in human cancer and is crucial for cancer cell growth and survival. Liu and colleagues discuss key therapeutic targets in the PI3K pathway and agents that are currently in development, and consider the associated challenges and possible approaches to overcome them.
Immune tolerance might be therapeutically manipulated to restore normal immunity in allergic disease. This Review highlights current knowledge of immunomodulatory therapies for the manipulation of immune tolerance and discusses recent approaches to improve allergen-specific immunotherapy.
The dysregulated activity of protein kinases is commonly implicated in human cancers, and many anti-cancer agents aiming to inhibit specific kinases are now approved or under investigation. Here, Settleman and colleagues discuss factors responsible for the variability in clinical sensitivity to small-molecule kinase inhibitors that should be considered in the development and use of new agents.