Showing papers in "Nature Reviews Drug Discovery in 2007"
TL;DR: The experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years is shared, and what is learned is looked at and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
Abstract: The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
2,228 citations
TL;DR: Viewing the process of angiogenesis as an 'organizing principle' in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained for the clinical use ofAngiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but also for developing therapeutic approaches for various diseases that are otherwise unrelated to each other.
Abstract: Angiogenesis--the process of new blood-vessel growth--has an essential role in development, reproduction and repair. However, pathological angiogenesis occurs not only in tumour formation, but also in a range of non-neoplastic diseases that could be classed together as 'angiogenesis-dependent diseases'. By viewing the process of angiogenesis as an 'organizing principle' in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained. This has important consequences for the clinical use of angiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but possibly also for developing therapeutic approaches for various diseases that are otherwise unrelated to each other.
1,990 citations
TL;DR: Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.
Abstract: The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.
1,954 citations
TL;DR: This Review focuses on pharmacological strategies to attenuate the toxic effects of peroxynitrite, which include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases.
Abstract: Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases
1,804 citations
TL;DR: The physiology and biochemistry of H2S is overviews, the effects of H 2S inhibitors or H2s donors in animal models of disease are summarized, the potential options for the therapeutic exploitation of H1S are outlined and they are outlined.
Abstract: Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.
1,639 citations
TL;DR: The mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs are detailed and a perspective on the possible future applications of lipid-based delivery systems is provided.
Abstract: Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.
1,550 citations
TL;DR: The considerations that go into developing RNAi-based therapeutics starting from in vitro lead design and identification, to in vivo pre-clinical drug delivery and testing are discussed and the latest clinical experience with RNAi therapeutics is reviewed.
Abstract: RNA interference (RNAi) quietly crept into biological research in the 1990s when unexpected gene-silencing phenomena in plants and flatworms first perplexed scientists. Following the demonstration of RNAi in mammalian cells in 2001, it was quickly realized that this highly specific mechanism of sequence-specific gene silencing might be harnessed to develop a new class of drugs that interfere with disease-causing or disease-promoting genes. Here we discuss the considerations that go into developing RNAi-based therapeutics starting from in vitro lead design and identification, to in vivo pre-clinical drug delivery and testing. We conclude by reviewing the latest clinical experience with RNAi therapeutics.
1,207 citations
TL;DR: The goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.
Abstract: The family of interferon (IFN) proteins has now more than reached the potential envisioned by early discovering virologists: IFNs are not only antivirals with a spectrum of clinical effectiveness against both RNA and DNA viruses, but are also the prototypic biological response modifiers for oncology, and show effectiveness in suppressing manifestations of multiple sclerosis. Studies of IFNs have resulted in fundamental insights into cellular signalling mechanisms, gene transcription and innate and acquired immunity. Further elucidation of the multitude of IFN-induced genes, as well as drug development strategies targeting IFN production via the activation of the Toll-like receptors (TLRs), will almost certainly lead to newer and more efficacious therapeutics. Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.
1,069 citations
TL;DR: Advances in lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics are reviewed.
Abstract: Remarkably, with the exception of anaesthetic gases, the ancient human practice of inhaling substances into the lungs for systemic effect has only just begun to be adopted by modern medicine. Treatment of asthma by inhaled drugs began in earnest in the 1950s, and now such 'topical' or targeted treatment with inhaled drugs is considered for treating many other lung diseases. More recently, major advances have led to increasing interest in systemic delivery of drugs by inhalation. Small molecules can be delivered with very rapid action, low metabolism and high bioavailability; and macromolecules can be delivered without injections, as highlighted by the recent approval of the first inhaled insulin product. Here, we review these advances, and discuss aspects of lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics.
1,061 citations
TL;DR: A better understanding of autophagy is needed to allow its manipulation for therapeutic purposes, and new insights into the molecular mechanisms are now leading to the discovery of exciting new potential drug targets.
Abstract: Autophagy is a dynamic process of subcellular degradation, which has recently sparked great interest as it is now recognized to be involved in various developmental processes and various diseases including cancer and neurodegeneration. Autophagy can function as a cytoprotective mechanism; however, it also has the capacity to cause cell death. A better understanding of autophagy is needed to allow its manipulation for therapeutic purposes, and new insights into the molecular mechanisms of autophagy are now leading to the discovery of exciting new potential drug targets.
994 citations
TL;DR: The development and evolution of fragment-based drug design is described, the role that this approach can have in combination with other discovery technologies and the impact that fragment- based methods have made in progressing new medicines into the clinic are highlighted.
Abstract: Since the early 1990s, several technological and scientific advances - such as combinatorial chemistry, high-throughput screening and the sequencing of the human genome - have been heralded as remedies to the problems facing the pharmaceutical industry. The use of these technologies in some form is now well established at most pharmaceutical companies; however, the return on investment in terms of marketed products has not met expectations. Fragment-based drug design is another tool for drug discovery that has emerged in the past decade. Here, we describe the development and evolution of fragment-based drug design, analyse the role that this approach can have in combination with other discovery technologies and highlight the impact that fragment-based methods have made in progressing new medicines into the clinic.
TL;DR: It is argued that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes, and emerging data indicate that TRPs could be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome.
Abstract: The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.
TL;DR: This Review compares the major classes of MMP inhibitors and advocates that future drug discovery should be based on crucial insights into the differential roles of specific MMPs in pathophysiology obtained with animal models, including knockout studies.
Abstract: Matrix metalloproteinases (MMPs) have outgrown the field of extracellular-matrix biology and have progressed towards being important regulatory molecules in cancer and inflammation. This rise in status was accompanied by the development of various classes of inhibitors. Although clinical trials with synthetic inhibitors for the treatment of cancer were disappointing, recent data indicate that the use of selective inhibitors might lead to new therapies for acute and chronic inflammatory and vascular diseases. In this Review, we compare the major classes of MMP inhibitors and advocate that future drug discovery should be based on crucial insights into the differential roles of specific MMPs in pathophysiology obtained with animal models, including knockout studies.
TL;DR: The potential of peptide-based vaccines for the treatment of chronic viral diseases and cancer, and the discovery of unusually long cytotoxic T-lymphocyte epitopes broaden the range of targets and give clues to enhancing peptide immunogenicity.
Abstract: The use of peptides as therapeutics is experiencing renewed enthusiasm owing to advances in delivery, stability and design. Moreover, there is a growing emphasis on the use of peptides in vaccine design as insights into tissue-specific processing of the immunogenic epitopes of proteins and the discovery of unusually long cytotoxic T-lymphocyte epitopes broaden the range of targets and give clues to enhancing peptide immunogenicity. Peptides can also be synthesized with known post-translational modifications and/or deliberately introduced protease-resistant peptide bonds to regulate their processing independent of tissue-specific proteolysis and to stabilize these compounds in vivo. We discuss the potential of peptide-based vaccines for the treatment of chronic viral diseases and cancer, and review recent developments in the field of peptide-based vaccines.
TL;DR: The polyamines spermidine and spermine and their diamine precursor putrescine are naturally occurring, polycationic alkylamines that are essential for eukaryotic cell growth and are frequently dysregulated in cancer and other hyperproliferative diseases.
Abstract: The polyamines spermidine and spermine and their diamine precursor putrescine are naturally occurring, polycationic alkylamines that are essential for eukaryotic cell growth. The requirement for and the metabolism of polyamines are frequently dysregulated in cancer and other hyperproliferative diseases, thus making polyamine function and metabolism attractive targets for therapeutic intervention. Recent advances in our understanding of polyamine function, metabolic regulation, and differences between normal cells and tumour cells with respect to polyamine biology, have reinforced the interest in this target-rich pathway for drug development.
TL;DR: Key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors are discussed.
Abstract: Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors
TL;DR: A historical perspective on the discovery and development of two inhibitors of sialidase — zanamivir and oseltamiviral — is provided and highlights the value of structure-based drug design in this process.
Abstract: The threat of an influenza pandemic has heightened the need for therapeutic strategies to combat this virus. This article provides a historical perspective on the discovery and development of two drugs that are at the forefront of our defences against influenza — the sialdiase inhibitors zanamivir and oseltamivir — highlighting the value of structure-based drug design in this process. The threat of a major human influenza pandemic, in particular from highly aggressive strains such as avian H5N1, has emphasized the need for therapeutic strategies to combat these pathogens. At present, two inhibitors of sialidase (also known as neuraminidase), a viral enzyme that has a key role in the life cycle of influenza viruses, would be the mainstay of pharmacological strategies in the event of such a pandemic. This article provides a historical perspective on the discovery and development of these drugs — zanamivir and oseltamivir — and highlights the value of structure-based drug design in this process.
TL;DR: An improved understanding of the regulatory interfaces that exist between blood and brain may provide novel and more effective strategies to treat neurological disorders.
Abstract: The market for neuropharmaceuticals is potentially one of the largest sectors of the global pharmaceutical market owing to the increase in average life expectancy and the fact that many neurological disorders have been largely refractory to pharmacotherapy. The brain is a delicate organ that can efficiently protect itself from harmful compounds and precisely regulate its microenvironment. Unfortunately, the same mechanisms can also prove to be formidable hurdles in drug development. An improved understanding of the regulatory interfaces that exist between blood and brain may provide novel and more effective strategies to treat neurological disorders.
TL;DR: Specific mAChR-regulated pathways are identified as potentially novel targets for the treatment of various important disorders including Alzheimer's disease, schizophrenia, pain, obesity and diabetes.
Abstract: Muscarinic acetylcholine receptors (mAChRs), M(1)-M(5), regulate the activity of numerous fundamental central and peripheral functions. The lack of small-molecule ligands that can block or activate specific mAChR subtypes with high selectivity has remained a major obstacle in defining the roles of the individual receptor subtypes and in the development of novel muscarinic drugs. Recently, phenotypic analysis of mutant mouse strains deficient in each of the five mAChR subtypes has led to a wealth of new information regarding the physiological roles of the individual receptor subtypes. Importantly, these studies have identified specific mAChR-regulated pathways as potentially novel targets for the treatment of various important disorders including Alzheimer's disease, schizophrenia, pain, obesity and diabetes.
TL;DR: An effort to build virtual populations using extensive demographic, physiological, genomic and in vitro biochemical data to simulate and predict drug disposition from routinely collected in vitro data is outlined.
Abstract: The perceived failure of new drug development has been blamed on deficiencies in in vivo studies of drug efficacy and safety. Prior simulation of the potential exposure of different individuals to a given dose might help to improve the design of such studies. This should also help researchers to focus on the characteristics of individuals who present with extreme reactions to therapy. An effort to build virtual populations using extensive demographic, physiological, genomic and in vitro biochemical data to simulate and predict drug disposition from routinely collected in vitro data is outlined.
TL;DR: Current and emerging examples in which therapies are matched with specific patient population characteristics using clinical biomarkers — which is called stratified medicine — are considered and the implications of this approach to future product development strategies and market structures are discussed.
Abstract: The potential to use biomarkers for identifying patients that are more likely to benefit or experience an adverse reaction in response to a given therapy, and thereby better match patients with therapies, is anticipated to have a major effect on both clinical practice and the development of new drugs and diagnostics. In this article, we consider current and emerging examples in which therapies are matched with specific patient population characteristics using clinical biomarkers - which we call stratified medicine - and discuss the implications of this approach to future product development strategies and market structures.
TL;DR: This work uses examples that are based on existing drugs to illustrate the concept of robustness, and discusses how a greater consideration of the importance of robustity could influence the design of new drugs that will be intended to control complex systems.
Abstract: Many potential drugs that specifically target a particular protein considered to underlie a given disease have been found to be less effective than hoped, or to cause significant side effects. The intrinsic robustness of living systems against various perturbations is a key factor that prevents such compounds from being successful. By studying complex network systems and reformulating control and communication theories that are well established in engineering, a theoretical foundation for a systems-oriented approach to more effectively control the robustness of living systems, particularly at the cellular level, could be developed. Here, I use examples that are based on existing drugs to illustrate the concept of robustness, and then discuss how a greater consideration of the importance of robustness could influence the design of new drugs that will be intended to control complex systems.
TL;DR: The challenges and opportunities for therapeutic strategies based on RXR and RAR modulators, with a focus on cancer and metabolic diseases such as diabetes and obesity, are discussed.
Abstract: Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. The success of RAR modulation in the treatment of acute promyelocytic leukaemia (APL) has stimulated considerable interest in the development of RAR and RXR modulators. This has been aided by recent advances in the understanding of the biological role of RARs and RXRs and in the design of selective receptor modulators that might overcome the limitations of current drugs. Here, we discuss the challenges and opportunities for therapeutic strategies based on RXR and RAR modulators, with a focus on cancer and metabolic diseases such as diabetes and obesity.
TL;DR: From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdueimmune responses in cancers, infectious diseases or inflammatory disorders.
Abstract: Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). The regulated expression and activity of DUSP family members in different cells and tissues controls MAPK intensity and duration to determine the type of physiological response. For immune cells, DUSPs regulate responses in both positive and negative ways, and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of immune responses. From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdue immune responses in cancers, infectious diseases or inflammatory disorders.
TL;DR: In this article, the authors review emerging druggable targets and novel therapeutic approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.
Abstract: The involvement of the RAS superfamily of monomeric GTPases in carcinogenesis is increasingly being appreciated. A complex array of post-translational modifications and a highly sophisticated protein network regulate the spatio-temporal activation of these GTPases. Previous attempts to pharmacologically target this family have focused on the development of farnesyltransferase inhibitors, but the performance of such agents in cancer clinical trials has not been as good as hoped. Here, we review emerging druggable targets and novel therapeutic approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.
TL;DR: Recent evidence supporting the validity of the three most relevant kinases affecting tau hyperphosphorylation — GSK3β, CDK5 and ERK2 — as drug targets is considered and progress in the design of inhibitors for these kinases is described.
Abstract: Aggregation of hyperphosphorylated tau is one of the characteristic neuropathological lesions of Alzheimer's disease and other neurodegenerative disorders. Pharmacological modulation of tau hyperphosphorylation might represent a valid and feasible therapeutic strategy for such disorders. Here, we consider recent evidence supporting the validity of the three most relevant kinases affecting tau hyperphosphorylation - GSK3beta, CDK5 and ERK2 - as drug targets and describe progress in the design of inhibitors for these kinases.
TL;DR: Trends in the clinical development and regulatory approval of monoclonal antibodies for cancer since 1980 are overviewed with the aim of informing future research and development for this class of therapeutics.
Abstract: Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases. Owing to the ability of these agents to selectively target tumour cells, cancer has been a major focus of development programmes for monoclonal antibodies so far. Here, we overview trends in the clinical development and regulatory approval of monoclonal antibodies for cancer since 1980, with the aim of informing future research and development for this class of therapeutics.
TL;DR: Here, the broad panel of experimental strategies that can be applied to target deconvolution is critically reviewed.
Abstract: Recognition of some of the limitations of target-based drug discovery has recently led to the renaissance of a more holistic approach in which complex biological systems are investigated for phenotypic changes upon exposure to small molecules. The subsequent identification of the molecular targets that underlie an observed phenotypic response--termed target deconvolution--is an important aspect of current drug discovery, as knowledge of the molecular targets will greatly aid drug development. Here, the broad panel of experimental strategies that can be applied to target deconvolution is critically reviewed.
TL;DR: Considering the drug targets in the different stages of the life cycle of these two viruses, aspects of the history, medicinal chemistry and mechanisms of action of approved and investigational drugs for HIV and HCV are presented and general lessons learned from anti-HIV-drug design are highlighted.
Abstract: Drug development for HIV has been the major driving force in antiviral research The strategies that are now being pursued for combating hepatitis C virus (HCV) are remarkably reminiscent of those established for HIV Here, De Clercq reviews aspects of the medicinal chemistry and history of drug design for HIV and HCV
TL;DR: Three specific SADRs are discussed with an emphasis on genetic risk factors, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug- induced long QT and torsades de pointes.
Abstract: Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drug's pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic. Genetic factors may underlie susceptibility to SADRs and the identification of predisposing genotypes may improve patient management through the prospective selection of appropriate candidates. Here we discuss three specific SADRs with an emphasis on genetic risk factors. These SADRs, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes. Key challenges for the discovery of predictive risk alleles for these SADRs are also considered.