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Many G protein-coupled receptors (GPCRs) are involved in the initiation and/or progression of cancer. Here, the authors discuss recent advances regarding the involvement of GPCRs in cancer and address the implications of these findings towards the discovery of innovative drug targets for cancer prevention and treatment.
The anticoagulant rivaroxaban is the first approved direct inhibitor of the serine protease factor Xa. This article presents the history of rivaroxaban's development, from its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.
Implicit in criticism of 'follow on' or 'me too' drugs is the idea that their development occurs after a first-in-class drug has made it to market and proved commercially successful. Using analysis of development and patent filing histories of entrants to new drug classes in the past five decades, this article provides new evidence that the development of multiple new drugs in a given class is better characterized as a race, rather than the imitation of successful products.
The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis, and their functional importance in various diseases, including cancer, cardiovascular disease and neurodegenerative disorders, is now beginning to emerge. Brownell and colleagues review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention.
Data on the fraction of protein-bound drug are frequently used to guide chemical structure design and to prioritize compounds forin vivostudies. Here, the authors highlight how these practices are misleading and could result in the wrong compounds being progressed through discovery programmes.
The expression of TSPO, a mitochondrial translocator protein involved in steroid synthesis, in the nervous system is altered in numerous neurological and psychiatric conditions. Rupprecht and colleagues review the potential of TSPO ligands for the treatment and diagnosis of disorders including anxiety, neuropathic pain and amyotrophic lateral sclerosis.
Here, the authors discuss the potential of tyrosine kinase inhibitors — currently used for the treatment of cancer — as anti-proliferative agents in non-malignant disorders such as cardiac hypertrophy, pulmonary hypertension, lung fibrosis and rheumatoid disorders.
The vitamin D endocrine system is a well-established target for metabolic bone disorders. Furthermore, the identification of the vitamin D receptor in tissues not related to calcium and bone has stimulated interest in its therapeutic significance in autoimmune diseases, cardiovascular disorders, infectious diseases and cancer. Plum and DeLuca highlight the emerging opportunities for vitamin D-based therapies in those diseases for which the evidence of their potential is most compelling.
Regulatory and economic incentives to develop drugs for rare diseases, known as orphan drugs, have resulted in substantial improvements in the treatment for patients with some such diseases. However, the advent of orphan drug development has also raised several questions, from the definition of rarity, to the pricing of orphan drugs and their impact on health-care systems. Tambuyzer considers such questions and related misconceptions with the aim of aiding future progress in the field.
In September 2010, fingolimod (FTY720/Gilenya; Novartis) became the first oral disease-modifying therapy to be approved by the US Food and Drug Administration for relapsing–remitting multiple sclerosis. Brinkmann and colleagues describe its discovery and development, and how elucidation of its effects on sphingosine 1-phosphate receptors has improved the understanding of the biology of these receptors.
Developing optimal combination strategies for molecularly targeted anticancer drugs is substantially more complex than for traditional chemotherapies. Here, Doroshow and colleagues discuss the lessons learned from the evaluation of combinations of molecularly targeted anticancer agents by the US National Cancer Institute (NCI), and highlight several new approaches that the NCI has initiated to improve the effectiveness of such combinations.
MicroRNAs (miRNAs) are attracting increasing attention as promising targets for the treatment of cancer. Here, the authors discuss the role of miRNAs in cancer development, and discuss the rationale, the strategies and the challenges for developing therapeutics that modulate miRNAs.
Integrins — a large family of cell adhesion molecules — have been extensively investigated as targets for diseases including thrombosis, cancer and autoimmune disorders. This article discusses how recent advances in understanding of integrin structure, function, ligand interaction and signalling pathways, as well as lessons learned from first-generation integrin antagonists, are indicating novel strategies for inhibiting integrins that could help exploit their full therapeutic potential.
Compounds that alter microtubule function can be highly active in patients with cancer. Here, the authors review the mechanisms of action of and resistance to microtubule-binding agents, then highlight novel anticancer microtubule-binding agents that have recently been approved or reached clinical trials.
Currently, drug development is based on a consecutive phase model and Phase I clinical trials often have tolerability as their primary objective. Here, Cohen advocates new concepts for drug development that are based on pharmacological knowledge about the effects of the drug and an adaptive, cyclical development process.
Fully human monoclonal antibodies (mAbs), which have the potential to be less immunogenic than earlier humanized and chimeric mAbs, are the most rapidly growing class of mAbs in clinical development. Here, Reichert and colleagues highlight trends in the development of human mAbs, seven of which have so far gained regulatory approval.
Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule. Here, the authors review the physiology of CO, summarize the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discuss the therapeutic development of this gaseous molecule.
The development of new protease inhibitors has proved challenging in recent years. In their Perspective, Drag and Salvesen discuss the underlying reasons for this, and how lessons learned from failures can inform future research directions in the field.
Cytokines — key instigators and regulators of immune responses — hold potential as targets for new therapeutic strategies. Here, Kopf and colleagues highlight some of the most effective and promising cytokine targets that have been linked to inflammatory diseases in preclinical and clinical studies and discuss some of the issues facing the development of cytokine-targeted drugs.
A lack of entrepreneurial behaviour has often been identified as a contributor to the decline in the research and development (R&D) productivity of the pharmaceutical industry. Douglas and colleagues present an assessment of entrepreneurship in the industry, based on interviews with 26 former and current leaders of R&D departments at pharmaceutical and biotechnology companies, highlighting factors that could be important in promoting entrepreneurial behaviour and revitalizing R&D productivity.