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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.
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.
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 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.
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.
Cell surface carbohydrates and carbohydrate-binding proteins mediate many key recognition events. This article reviews current progress in the development of glycomimetics and the opportunities and challenges presented by this relatively untapped source of therapeutics.
Aberrant activity of cell cycle protein kinases, leading to uncontrolled cell proliferation, is a hallmark of human cancer. Here, Lapenna and Giordano review recent progress in the modulation of specific protein kinase activity for the treatment of various cancers and identify novel strategies for the design of new agents.
Here, the authors summarize the current state of multi-parameter profiling technologies and how phenotypic profiling of small molecules provides important insights into their mechanisms of action, as well as a systems level understanding of biological pathways and their responses to drug treatments.
In this Review, the authors emphasize a translational approach to pharmacotherapy development for the treatment of drug addiction, whereby existing medications are used to validate and improve animal and human laboratory models to identify potential new therapies.
Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular sensors that have key roles in innate immunity and inflammation. This Review discusses the effect that research on NLRs will have on vaccination, treatment of chronic inflammatory disorders and acute bacterial infections.
A chronic inflammatory state, leading to local and systemic deleterious effects on host cells and tissues, is maintained in several diseases. Here, Gaestel and colleagues review current understanding of the roles and molecular mechanisms of kinase signalling in inflammation, emphasizing the most recent advances in the development of specific small-molecule kinase inhibitors for the treatment of chronic inflammation.
Drug resistance and the genomic instability of cancer cells hamper current gene-targeting therapeutic strategies for cancer. As Huang and colleagues discuss, targeting the unique biochemical properties of cancer cells — in particular, increased oxidative stress — might represent an alternative approach for the development of selective, redox-modulating anticancer agents.