Drug Discovery Today

Exosomes: a new horizon in lung cancer ()
Publication date: Available online 10 March 2017 Source:Drug Discovery Today Author(s): Irene Vanni, Angela Alama, Francesco Grossi, Maria Giovanna Dal Bello, Simona Coco Circulating exosomes are the major mediators of cell–cell communication. They have been found in various body fluids of healthy individuals and patients with malignancies as cargos of several molecules including miRNAs. Several studies have underlined the role of exosome miRNAs in different tumor types, including lung cancer, suggesting their potential use as biomarkers and therapeutic agents. An overview of the biology and function of exosomes and exosome miRNAs as indicators of diagnosis and treatment response in lung cancer is presented. In addition, preliminary data on exosomes as potential therapeutic agents are reported.
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Factors related to drug approvals: predictors of outcome? ()
Publication date: Available online 10 March 2017 Source:Drug Discovery Today Author(s): Lawrence Liberti, Alasdair Breckenridge, Jarno Hoekman, Neil McAuslane, Pieter Stolk, Hubert Leufkens There is growing interest in characterising factors associated with positive regulatory outcomes for drug marketing authorisations. We assessed empirical studies published over the past 15 years seeking to identify predictive factors. Factors were classified to one of four ‘factor clusters’: evidentiary support; product or indication characteristics; company experience or strategy; social and regulatory factors. We observed a heterogeneous mix of technical factors (e.g., study designs, clinical evidence of efficacy) and less studied social factors (e.g., company–regulator interactions). We confirmed factors known to be of relevance to drug approval decisions (imperative) and a cohort of less understood (compensatory) social factors. Having robust supportive clinical evidence, addressing rare or serious illness, following scientific advice and prior company experience were associated with positive outcomes, which illustrated the multifactorial nature of regulatory decision making and factors need to be considered holistically while having varying, context-dependent importance.
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Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins ()
Publication date: Available online 8 March 2017 Source:Drug Discovery Today Author(s): Cristina Banfi, Roberta Baetta, Erica Gianazza, Elena Tremoli Proteomic-based techniques provide a powerful tool for identifying the full spectrum of protein targets of a drug, elucidating its mechanism(s) of action, and identifying biomarkers of its efficacy and safety. Herein, we outline the technological advancements in the field, and illustrate the contribution of proteomics to the definition of the pharmacological profile of statins, which represent the cornerstone of the prevention and treatment of cardiovascular diseases (CVDs). Statins act by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thus reducing cholesterol biosynthesis and consequently enhancing the clearance of low-density lipoproteins from the blood; however, HMG-CoA reductase inhibition can result in a multitude of additional effects beyond lipid lowering, known as ‘pleiotropic effects’. The case of statins highlights the unique contribution of proteomics to the target profiling of a drug molecule. This review describes the methodological and technological improvements in the field of proteomics and how proteomic-based techniques represent a powerful tool to globally analyse the spectrum of pharmacological drug targets.
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Containment challenges in HPAPI manufacture for ADC generation ()
Publication date: Available online 6 March 2017 Source:Drug Discovery Today Author(s): Elizabeth Dunny, Imelda O’Connor, Jonathan Bones Antibody–drug conjugates (ADCs) are emerging as an impactful class of therapeutics for the treatment of cancer because of their ability to harness the specificity of an antibody and the cytotoxic potential of the payload to target and destroy cancer cells. However, the potent nature of the cytotoxic payload creates associated manufacturing challenges for active pharmaceutical ingredient (API) manufacturers, because huge investment in containment technology is required to ensure the protection of operators and the environment. Here, we examine the differing attitudes to high-potency categorisation and levels of containment control. We also provide an overview of the most widely used containment strategies for facility design, powder handling, purification, analysis, and cleaning. Finally, we briefly consider the health and safety regulatory challenges associated with the manufacture of antibody–drug conjugates.
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Systemic QSAR and phenotypic virtual screening: chasing butterflies in drug discovery ()
Publication date: Available online 6 March 2017 Source:Drug Discovery Today Author(s): Maykel Cruz-Monteagudo, Stephan Schürer, Eduardo Tejera, Yunierkis Pérez-Castillo, José L. Medina-Franco, Aminael Sánchez-Rodríguez, Fernanda Borges Current advances in systems biology suggest a new change of paradigm reinforcing the holistic nature of the drug discovery process. According to the principles of systems biology, a simple drug perturbing a network of targets can trigger complex reactions. Therefore, it is possible to connect initial events with final outcomes and consequently prioritize those events, leading to a desired effect. Here, we introduce a new concept, ‘Systemic Chemogenomics/Quantitative Structure–Activity Relationship (QSAR)’. To elaborate on the concept, relevant information surrounding it is addressed. The concept is challenged by implementing a systemic QSAR approach for phenotypic virtual screening (VS) of candidate ligands acting as neuroprotective agents in Parkinson’s disease (PD). The results support the suitability of the approach for the phenotypic prioritization of drug candidates. Graphical abstract image Systemic chemogenomics/QSAR is a new concept that forms the basis for a phenotypic virtual screening approach in drug discovery.
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The use of nanoscaffolds and dendrimers in tissue engineering ()
Publication date: Available online 20 February 2017 Source:Drug Discovery Today Author(s): Bapi Gorain, Muktika Tekade, Prashant Kesharwani, Arun K. Iyer, Kiran Kalia, Rakesh Kumar Tekade To avoid tissue rejection during organ transplantation, research has focused on the use of tissue engineering to regenerate required tissues or organs for patients. The biomedical applications of hyperbranched, multivalent, structurally uniform, biocompatible dendrimers in tissue engineering include the mimicking of natural extracellular matrices (ECMs) in the 3D microenvironment. Dendrimers are unimolecular architects that can incorporate a variety of biological and/or chemical substances in a 3D architecture to actively support the scaffold microenvironment during cell growth. Here, we review the use of dendritic delivery systems in tissue engineering. We discuss the available literature, highlighting the 3D architecture and preparation of these nanoscaffolds, and also review challenges to, and advances in, the use dendrimers in tissue engineering. Advances in the manufacturing of dendritic nanoparticles and scaffold architectures have resulted in the successful incorporation of dendritic scaffolds in tissue engineering.
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The importance of the glycosylation of antimicrobial peptides: natural and synthetic approaches ()
Publication date: Available online 16 February 2017 Source:Drug Discovery Today Author(s): Natalia G. Bednarska, Brendan W. Wren, Sam J. Willcocks Glycosylation is one of the most prevalent post-translational modifications of a protein, with a defining impact on its structure and function. Many of the proteins involved in the innate or adaptive immune response, including cytokines, chemokines, and antimicrobial peptides (AMPs), are glycosylated, contributing to their myriad activities. The current availability of synthetic coupling and glycoengineering technology makes it possible to customise the most beneficial glycan modifications for improved AMP stability, microbicidal potency, pathogen specificity, tissue or cell targeting, and immunomodulation.
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Is the European regulatory framework sufficient to assure the safety of citizens using health products containing nanomaterials? ()
Publication date: Available online 9 February 2017 Source:Drug Discovery Today Author(s): Umberto M. Musazzi, Valentina Marini, Antonella Casiraghi, Paola Minghetti The growing application of nanomaterials in healthcare products (i.e., cosmetics, medical devices, and medicinal products) has encouraged the upgrade of the regulatory framework within the European Community to better control their use and manage the risk of negative effects on human health and environment. Unfortunately, despite the efforts of European Authorities, the current legislation is still stratified and several criticisms remain because of the lack of well-established scientific knowledge on nanomaterials. Although the regulatory framework for cosmetic products is almost complete, the efficacy and/or safety assessment of nanomaterials in medicinal products and medical devices is still based on case-by-case evaluation because of the complexity of such systems. The review examines the stratified regulatory framework concerning the use of nanomaterials in healthcare products intended to be marketed in the European Economic Area, and highlights the current criticisms associated with the framework.
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Emerging RNA editing biomarkers will foster drug development ()
Publication date: Available online 7 February 2017 Source:Drug Discovery Today Author(s): Siem van der Laan, Nicolas Salvetat, Dinah Weissmann, Franck Molina Unanticipated adverse drug reactions (ADRs) on the central nervous system are a major cause of clinical attrition and market withdrawal. Current practices for their prospective assessment still lean on extensive analysis of rodent behaviour despite their highly controversial predictive value. Human-derived in vitro models that objectively quantify mechanism-related biomarkers can greatly contribute to better ADR prediction at early developmental stages. Adenosine-to-inosine RNA editing constitutes a physiological cellular process that translates environmental cues by regulating protein function at the synaptic level in health and disease. Robust solutions based on NGS-based quantification of RNA editing biomarkers have emerged to predict the likelihood of treatment-related suicidal ideation and behaviour allowing cost-effective high-throughput drug screening as a strategy for risk mitigation. Technological progress opens the way for accurate quantification of RNA editing modifications that will provide insightful information on drug-emergent phenomena at various stages during development
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Bringing new dimensions to drug discovery screening: impact of cellular stimulation technologies ()
Publication date: Available online 4 February 2017 Source:Drug Discovery Today Author(s): Elena Molokanova, Mark Mercola, Alex Savchenko The current mandate for the drug discovery industry is to develop more efficient drugs faster while reducing the costs associated with their development. Incorporation of cell stimulation technologies during screening assays is expected to revolutionize the discovery of novel drugs as well as safety pharmacology. In this review, we highlight ‘classical’ and emerging cell stimulation technologies that provide the ability to evaluate the effects of drug candidates on cells in different functional states to assess clinically relevant phenotypes. The dynamic stimulation of cells during drug screening helps to make the drug discovery process more efficient. Here, we review ‘classic’ and emerging cellular stimulation technologies that are compatible with optical screening assays.
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Next-generation sequencing: big data meets high performance computing ()
Publication date: Available online 2 February 2017 Source:Drug Discovery Today Author(s): Bertil Schmidt, Andreas Hildebrandt The progress of next-generation sequencing has a major impact on medical and genomic research. This high-throughput technology can now produce billions of short DNA or RNA fragments in excess of a few terabytes of data in a single run. This leads to massive datasets used by a wide range of applications including personalized cancer treatment and precision medicine. In addition to the hugely increased throughput, the cost of using high-throughput technologies has been dramatically decreasing. A low sequencing cost of around US$1000 per genome has now rendered large population-scale projects feasible. However, to make effective use of the produced data, the design of big data algorithms and their efficient implementation on modern high performance computing systems is required.
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Contents page 1 ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2
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Contents page 2 ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2
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Are SAR tables obsolete? ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Celerino Abad-Zapatero
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The SULSA Assay Development Fund: accelerating translation of new biology from academia to pharma ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Stuart P. McElroy, Philip S. Jones, Denise V. Barrault With industry increasingly sourcing preclinical drug discovery projects from academia it is important that new academic discoveries are enabled through translation with HTS-ready assays. However, many scientifically interesting, novel molecular targets lack associated high-quality, robust assays suitable for hit finding and development. To bridge this gap, the Scottish Universities Life Sciences Alliance (SULSA) established a fund to develop assays to meet quality criteria such as those of the European Lead Factory. A diverse project portfolio was quickly assembled, and a review of the learnings and successful outcomes showed this fund as a new highly cost-effective model for leveraging significant follow-on resources, training early-career scientists and establishing a culture of translational drug discovery in the academic community.
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Semiconductor technology in protein kinase research and drug discovery: sensing a revolution ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Nikhil Bhalla, Mirella Di Lorenzo, Pedro Estrela, Giordano Pula Since the discovery of protein kinase activity in 1954, close to 600 kinases have been discovered that have crucial roles in cell physiology. In several pathological conditions, aberrant protein kinase activity leads to abnormal cell and tissue physiology. Therefore, protein kinase inhibitors are investigated as potential treatments for several diseases, including dementia, diabetes, cancer and autoimmune and cardiovascular disease. Modern semiconductor technology has recently been applied to accelerate the discovery of novel protein kinase inhibitors that could become the standard-of-care drugs of tomorrow. Here, we describe current techniques and novel applications of semiconductor technologies in protein kinase inhibitor drug discovery.
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Design of efficient computational workflows for in silico drug repurposing ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Quentin Vanhaelen, Polina Mamoshina, Alexander M. Aliper, Artem Artemov, Ksenia Lezhnina, Ivan Ozerov, Ivan Labat, Alex Zhavoronkov Here, we provide a comprehensive overview of the current status of in silico repurposing methods by establishing links between current technological trends, data availability and characteristics of the algorithms used in these methods. Using the case of the computational repurposing of fasudil as an alternative autophagy enhancer, we suggest a generic modular organization of a repurposing workflow. We also review 3D structure-based, similarity-based, inference-based and machine learning (ML)-based methods. We summarize the advantages and disadvantages of these methods to emphasize three current technical challenges. We finish by discussing current directions of research, including possibilities offered by new methods, such as deep learning. Teaser This review provides a comprehensive description of the conceptual foundation and computational developments in the field of in silico repurposing. Furthermore, a generic modular description for repurposing workflows is described.
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Amyloid beta modulators and neuroprotection in Alzheimer's disease: a critical appraisal ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Chandra Sekhar Kuruva, P. Hemachandra Reddy Multiple cellular changes have been identified as being involved in Alzheimer's disease (AD) pathogenesis, including mitochondrial damage, synaptic loss, amyloid beta (Aβ) production and/or accumulation, inflammatory responses, and phosphorylated tau formation and/or accumulation. Studies have established that Aβ-induced synaptic dysfunction is dependent on abnormal amyloid precursor protein (APP) processing caused by β- and γ-secretases, resulting in the generation of Aβ. The Aβ formed as a result of abnormal APP processing induces phosphorylated tau and activates glycogen synthase kinase-3β (GSK3β) and cyclin-dependent kinase-5 (CDK5). Here, we review the latest research on the development of Aβ modulators for neuroprotection in AD. We also review the use of molecular inhibitors as therapeutic targets in AD. Teaser This article highlights the latest research on the development of amyloid beta modulators for neuroprotection in Alzheimer's disease and also critically evaluates existing amyloid beta modulators as therapeutic targets in Alzheimer's disease.
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The next generation of antimicrobial peptides (AMPs) as molecular therapeutic tools for the treatment of diseases with social and economic impacts ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Nicolau B. da Cunha, Nicole B. Cobacho, Juliane F.C. Viana, Loiane A. Lima, Kamila B.O. Sampaio, Stephan S.M. Dohms, Arthur C.R. Ferreira, César de la Fuente-Núñez, Fabrício F. Costa, Octávio L. Franco, Simoni C. Dias Anti-infective drugs have had a key role in the contemporary world, contributing to dramatically decrease mortality rates caused by infectious diseases worldwide. Antimicrobial peptides (AMPs) are multifunctional effectors of the innate immune system of mucosal surfaces and present antimicrobial activity against a range of pathogenic viruses, bacteria, and fungi. However, the discovery and development of new antibacterial drugs is a crucial step to overcome the great challenge posed by the emergence of antibiotic resistance. In this review, we outline recent advances in the development of novel AMPs with improved antimicrobial activities that were achieved through characteristic structural design. In addition, we describe recent progress made to overcome some of the major limitations that have hindered peptide biosynthesis. Teaser This review provides an integrated scenario of the most relevant aspects in the development of useful drugs provided by natural sources and recent advances in the biosynthesis and structural design of antimicrobial peptides.
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Molecular dynamics-driven drug discovery: leaping forward with confidence ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Aravindhan Ganesan, Michelle L. Coote, Khaled Barakat Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery. From classical MD methods to more sophisticated hybrid classical/quantum mechanical (QM) approaches, MD simulations are now able to offer extraordinary insights into ligand–receptor interactions. In this review, we discuss how the applications of MD approaches are significantly transforming current drug discovery and development efforts. Teaser Molecular dynamics (MD) is an important tool that can offer significant benefits to structure-based drug design. This review addresses the theoretical background and various applications of MD that can transform the current drug discovery efforts.
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Doxorubicin: nanotechnological overviews from bench to bedside ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Maximiliano Cagel, Estefanía Grotz, Ezequiel Bernabeu, Marcela A. Moretton, Diego A. Chiappetta Doxorubicin (DOX) is considered one of the most effective chemotherapeutic agents, used as a first-line drug in numerous types of cancer. Nevertheless, it exhibits serious adverse effects, such as lethal cardiotoxicity and dose-limiting myelosuppression. In this review, we focus on the description and the clinical benefits of different DOX-loaded nanotechnological platforms, not only those commercially available but also the ones that are currently in clinical phases, such as liposomes, polymeric nanoparticles, polymer–drug conjugates, polymeric micelles and ligand-based DOX-loaded nanoformulations. Although some DOX-based nanoproducts are currently being used in the clinical field, it is clear that further research is necessary to achieve improvements in cancer therapeutics. Graphical abstract image Teaser This review provides an overview of the current state of the passively and actively targeted nanotechnological-based DOX formulations, some approved by regulatory agencies and others still in clinical trials.
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Downregulation of melanogenesis: drug discovery and therapeutic options ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Thanigaimalai Pillaiyar, Manoj Manickam, Sang-Hun Jung Melanin, primarily responsible in humans for hair, eye and skin pigmentation, is produced by melanocytes through a process called melanogenesis. However, the abnormal accumulation of melanin causes dermatological problems such as café-au-lait macules ephelides (freckles), solar lentigo (age spots) and melasma, as well as cancer and vitiligo. Hence the regulation of melanogenesis is very important for treating hyperpigmentary disorders. Numerous antimelanogenic agents that target tyrosinase activity and/or stability, melanosome maturation, transfer and trafficking, or melanogenesis-related signaling pathways have been developed. This article reviews recent advances in research and development of human tyrosinase and melanogenesis-related signaling pathway inhibitors. Attempts have been made to provide a complete description of the mechanism of action of inhibitors on various melanogenesis signaling pathways. The recent advances in research and development of human tyrosinase and melanogenesis-related signaling pathway inhibitors.
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Marine pharmacology: therapeutic targeting of matrix metalloproteinases in neuroinflammation ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Eugenia Gentile, Grazia M. Liuzzi Alterations in matrix metalloproteinase (MMP) expression and activity are recognized as key pathogenetic events in several neurological disorders. This evidence makes MMPs possible therapeutic targets. The search for substances that can inhibit MMPs is moving progressively toward the screening of natural products. In particular, marine bioprospecting could be promising for the discovery of marine natural products with anti-MMP activities. Despite recent advances in this field, the possibility of using marine MMP inhibitors (MMPIs) for the treatment of neuroinflammation is still under-investigated. Here, we review the latest findings in this promising research field and the potential that marine MMPIs can have in the management and treatment of various neurological diseases. This paper reviews the most recent findings in the search for anti-MMP molecules from marine invertebrates regarding their use in the management and treatment of neuroinflammation.
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Dendrimer nanoarchitectures for cancer diagnosis and anticancer drug delivery ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Ashok Kumar Sharma, Avinash Gothwal, Prashant Kesharwani, Hashem Alsaab, Arun K. Iyer, Umesh Gupta Dendrimers are novel nanoarchitectures with unique properties including a globular 3D shape, a monodispersed unimicellar nature and a nanometric size range. The availability of multiple peripheral functional groups and tunable surface engineering enable the facile modification of the dendrimer surface with different therapeutic drugs, diagnostic agents and targeting ligands. Drug encapsulation, and solubilizing and passive targeting also equally contribute to the therapeutic use of dendrimers. In this review, we highlight recent advances in the delivery of anticancer drugs using dendrimers, as well as other biomedical and diagnostic applications. Taken together, the immense potential and utility of dendrimers are envisaged to have a significant positive impact on the growing arena of drug delivery and targeting. Graphical abstract image Teaser Dendrimers are promising, efficient and smart nanocarriers with applications not only in drug delivery and targeting, but also in diagnosis. Host–guest chemistry, hyperbranched architecture and tailor-made surfaces make numerous surface-engineered dendrimer nanoarchitectures possible.
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Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Gillian R. Langley, Ian M. Adcock, François Busquet, Kevin M. Crofton, Elena Csernok, Christoph Giese, Tuula Heinonen, Kathrin Herrmann, Martin Hofmann-Apitius, Brigitte Landesmann, Lindsay J. Marshall, Emily McIvor, Alysson R. Muotri, Fozia Noor, Katrin Schutte, Troy Seidle, Anja van de Stolpe, Hilde Van Esch, Catherine Willett, Grzegorz Woszczek Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and non-governmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathways-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this. To discover and develop new therapies, we need 21st-century roadmaps for biomedical research based on multiscale human disease pathways, and supported by policy and funding strategies that prioritise human relevance.
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Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Mohammed Maniruzzaman, Ali Nokhodchi Currently, because globalization, the pharmaceutical industry is facing enormous challenges to comply with regulatory matters. Reduced patent life and overall decreased profitability of newly discovered drugs are also forcing the pharmaceutical industry to shorten the drug development time with maximum throughput. Therefore, continuous manufacturing (CM) processes via hot melt extrusion (HME) can be a promising alternative for achieving these goals. HME offers solvent-free green technology with a process that is easy to scale up. Moreover, CM provides better product quality assurance compared with batch processes, with fewer labor costs and shorter time to development. In this review, we primarily focus on various aspects of CM and the emerging application of HME to bridge the current manufacturing gap in pharmaceutical sphere. A solvent-free and easy to scale up HME can be implemented for continuous manufacturing of pharmaceuticals complying with the regulatory matters. HME is highly encouraged by a quality by design (QbD) viewpoint steered by the FDA.
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Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Werner J. Geldenhuys, Li Lin, Altaf S. Darvesh, Prabodh Sadana Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid levels. Although LPL expression and activity modulation is observed as a pleiotropic action of some the commonly used lipid lowering drugs, the deliberate development of drugs targeting LPL has not occurred yet. In this review, we present the biology of LPL, highlight the LPL modulation property of currently used drugs and review the novel emerging approaches to target LPL. Teaser Can modulating the levels of LPL regulatory proteins be a viable strategy to lower plasma lipids and attenuate metabolic diseases?
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Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Adriana Isvoran, Maxime Louet, Diana Larisa Vladoiu, Dana Craciun, Marie-Anne Loriot, Bruno O. Villoutreix, Maria A. Miteva Pharmacogenomics investigates DNA and RNA variations in the human genome related to drug responses. Cytochrome P450 (CYP) is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 90% of human drugs. Among the major CYP isoforms, the CYP2C subfamily is of clinical significance because it metabolizes approximately 20% of clinically administrated drugs and represents several variant alleles leading to adverse drug reactions or altering drug efficacy. Here, we review recent progress on understanding the interindividual variability of the CYP2C members and the functional and clinical impact on drug metabolism. We summarize current advances in the molecular modeling of CYP2C polymorphisms and discuss the structural bases and molecular mechanisms of amino acid variants of CYP2C members that affect drug metabolism.
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Molecular similarity considerations in the licensing of orphan drugs ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Pedro Franco, Nuria Porta, John D. Holliday, Peter Willett The large costs associated with modern drug discovery mean that governments and regulatory bodies need to provide economic incentives to promote the development of orphan drugs (i.e., medicinal products that are designed to treat rare disease that affect only small numbers of patients). Under European Union (EU) legislation, a medicine can only be authorised for treating a specific rare disease if it is not similar to other orphan drugs already authorised for that particular disease. Here, we discuss the use of 2D fingerprints to calculate the Tanimoto similarity between potential and existing orphan drugs for the same disease, and present logistic regression models correlating these computed similarities with the judgements of human experts.
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Bioimaging of nanoparticles: the crucial role of discriminating nanoparticles from free probes ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Xiongwei Hu, Xiaochun Dong, Yi Lu, Jianping Qi, Weili Zhao, Wei Wu The biological fate of nanocarriers has yet to be fully explored, mainly because of the lack of functional tools like probes to identify integral nanocarriers in the body. Understanding their in vivo fate remains as the bottleneck to the development of nanomedicines. Bioimaging results based on conventional fluorescent or radioactive probes should be judged critically because images merely reflect bulk signals of an admixture of the nanoparticles and free probes. It is crucial to discriminate between nanocarrier-bound and free signals. This review analyzes the state-of-the-art of bioimaging of nanoparticles in vivo and highlights directions for future endeavours.
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New concepts in asthma: clinical phenotypes and pathophysiological mechanisms ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Andreas R. Koczulla, Claus F. Vogelmeier, Holger Garn, Harald Renz Asthma is among the most common chronic inflammatory diseases worldwide. Recent evidence indicates that the pathogenesis shows a high degree of heterogeneity. Patient subsets have been identified that exhibit different cellular and molecular patterns of dysregulation. A prominent example is eosinophilic Th2-driven asthma. These unique and molecular patterns are termed endotypes. Characterization of endotypes has broad implications for therapeutic interventions. Although ∼80% of asthmatic patients respond well to standard anti-inflammatory therapies, the remaining subset particularly consisting of severe patients requires a more specialized endotype-specific approach. This interrelationship between clinical phenotypes, molecular endotypes and endotype-specific therapies is the focus of this review.
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Organs-on-chips: research and commercial perspectives ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Aarathi Balijepalli, Vaibhav Sivaramakrishan Traditional preclinical drug testing methods utilize animal models to predict pharmacology and toxicology profiles. However, the data obtained from such methods cannot be directly extrapolated to humans and often do not provide a safe starting dose for first-in-human studies. To overcome these limitations, researchers have developed organs-on-chips – microfluidic devices that can mimic the cellular architecture and physiology more accurately than conventional methods. Because accurate organ-level interactions can be achieved with these devices, they have the potential to provide a realistic determination of a drug's pharmacokinetics, pharmacodynamics and toxicity profile. In this review, we describe the evolution of the technology and provide an overview of its current applications. We also discuss the current industry and government initiatives in promoting further research on organs-on-chips for potential use during drug development.
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Global vision of druggability issues: applications and perspectives ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Hiba Abi Hussein, Colette Geneix, Michel Petitjean, Alexandre Borrel, Delphine Flatters, Anne-Claude Camproux During the preliminary stage of a drug discovery project, the lack of druggability information and poor target selection are the main causes of frequent failures. Elaborating on accurate computational druggability prediction methods is a requirement for prioritizing target selection, designing new drugs and avoiding side effects. In this review, we describe a survey of recently reported druggability prediction methods mainly based on networks, statistical pocket druggability predictions and virtual screening. An application for a frequent mutation of p53 tumor suppressor is presented, illustrating the complementarity of druggability prediction approaches, the remaining challenges and potential new drug development perspectives.
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Protein delivery to the back of the eye: barriers, carriers and stability of anti-VEGF proteins ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Krishna Radhakrishnan, Nirmal Sonali, Miguel Moreno, Jayabalan Nirmal, Alexandra A. Fernandez, Subbu Venkatraman, Rupesh Agrawal Utilization of the full clinical potential of many novel therapeutic proteins designed for diseases affecting the posterior segment of the eye has often been limited because of their inherent instability and the difficulty in overcoming various ocular barriers. Intravitreal injection is currently the only approved mode of administration, although it is suboptimal because it is painful and has to be done every 1–2 months as a result of high protein clearance rates from the vitreous humor. In this review, we discuss the status of protein drug delivery to back of the eye in terms of novel protein drugs developed, physiological barriers encountered, strategies for carrier design to overcome these limitations, and protein stability. We focus on the most promising approaches as well as on current shortcomings.
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miRNA nanotherapeutics for cancer ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Aditya Ganju, Sheema Khan, Bilal B. Hafeez, Stephen W. Behrman, Murali M. Yallapu, Subhash C. Chauhan, Meena Jaggi MicroRNAs (miRNAs) are noncoding RNA molecules that regulate gene expression through diverse mechanisms. Increasing evidence suggests that miRNA-based therapies, either restoring or repressing miRNA expression and activity, hold great promise. However, the efficient delivery of miRNAs to target tissues is a major challenge in the transition of miRNA therapy to the clinic. Cationic polymers or viral vectors are efficient delivery agents but their systemic toxicity and immunogenicity limit their clinical usage. Efficient targeting and sustained release of miRNAs/anti-miRNAs using nanoparticles (NPs) conjugated with antibodies and/or peptides could reduce the required therapeutic dosage while minimizing systemic and cellular toxicity. Given their importance in clinical oncology, here we focus on the development of miRNA nanoformulations to achieve enhanced cellular uptake, bioavailability, and accumulation at the tumor site.
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Fragmentation in the biopharmaceutical industry ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Andrew D. Goldsmith, Francisco E. Varela The large number of biopharmaceutical mergers and acquisitions (M&A) that occurred over the past decade has generated questions about whether the industry is consolidating around too-few players, negatively impacting both the number of medicines developed and overall innovation. However, closer examination of the level of biopharmaceutical consolidation by prescription sales shows that the industry was more fragmented in 2015 than in 2003. The trend towards increasing fragmentation is also observed across noncommercial and independent metrics over the same time period. The number and size of M&A deals has masked an active and competitive marketplace in which market growth and the number of companies entering the market exceeded the apparent reduction in the number of players caused by acquisitions.
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Mimicking the ocular environment for the study of inflammatory posterior eye disorders ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Nabeela K. Dulull, Thilini R. Thrimawithana, Faith A.A. Kwa The common inflammatory posterior eye disorders, age-related degeneration and glaucoma often lead to irreversible vision loss. Current treatments do not target early stages or prevent disease progression. Consequently, the identification of biomarkers or early disease models that can accurately mimic the pathological processes involved is essential. Although none of the existing models can recapitulate all pathological aspects of these disorders, these models have revealed new therapeutic targets. Efforts to accurately phenotype eye disorders at various disease stages are warranted to generate a ‘super’ model that can replicate the microenvironment of the eye and associated pathological hallmarks effectively.
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Designed covalent allosteric modulators: an emerging paradigm in drug discovery ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Shaoyong Lu, Jian Zhang Covalent allosteric modulators possess the pharmacological advantages (high potency, extended duration of action and low drug resistance) of covalent ligands and the additional benefit of the higher specificity and lower toxicity of allosteric modulators. This approach is gaining increasing recognition as a valuable tool in drug discovery. Here, we review the recent advances in the design of covalent allosteric modulators with an emphasis on successful examples. A broad spectrum of protein targets capable of being modulated by them reflects the prevalence of this strategy. We also discuss the challenges and future directions in the development of covalent allosteric modulators.
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Peptidomimetic therapeutics: scientific approaches and opportunities ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Nir Qvit, Samuel J.S. Rubin, Travis J. Urban, Daria Mochly-Rosen, Eric R. Gross Natural endogenously occurring peptides exhibit desirable medicinal properties, but are often limited in application by rapid proteolysis and inadequate membrane permeability. However, editing naturally occurring peptide sequences to develop peptidomimetic analogs created a promising class of therapeutics that can augment or inhibit molecular interactions. Here, we discuss a variety of chemical modifications, including l to d isomerization, cyclization, and unnatural amino acid substitution, as well as design strategies, such as attachment to cell-penetrating peptides, which are used to develop peptidomimetics. We also provide examples of approved peptidomimetics and discuss several compounds in clinical trials.
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UPLC–MS for metabolomics: a giant step forward in support of pharmaceutical research ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Ala F. Nassar, Terence Wu, Samuel F. Nassar, Adam V. Wisnewski Metabolomics is a relatively new and rapidly growing area of post-genomic biological research. As use of metabolomics technology grows throughout the spectrum of drug discovery and development, and its applications broaden, its impact is expanding dramatically. This review seeks to provide the reader with a brief history of the development of metabolomics, its significance and strategies for conducting metabolomics studies. The most widely used analytical tools for metabolomics: NMR, LC–MS and GC–MS, are discussed along with considerations for their use. Herein, we will show how metabolomics can assist in pharmaceutical research studies, such as pharmacology and toxicology, and discuss some examples of the importance of metabolomics analysis in research and development.
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The unique status of first-in-human studies: strengthening the social value requirement ()
Publication date: February 2017 Source:Drug Discovery Today, Volume 22, Issue 2 Author(s): Michelle G.J.L. Habets, Johannes J.M. van Delden, Annelien L. Bredenoord For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international research ethics guidelines. As there is a general positive attitude regarding the benefits of science, it is important to establish a more systematic method to assess anticipated social value to safeguard participants not only from enrolling in risky, but also in futile trials. Here, we provide some of necessary steps needed to assess the anticipated social value of the intervention.
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Safety of antisense oligonucleotide and siRNA-based therapeutics ()
Publication date: Available online 31 January 2017 Source:Drug Discovery Today Author(s): Xuan Chi, Philip Gatti, Thomas Papoian Oligonucleotide-based therapy is an active area of drug development designed to treat a variety of gene-specific diseases. Two of the more promising platforms are the antisense oligonucleotides (ASOs) and short interfering RNAs (siRNAs), both of which are often directed against similar targets. In light of recent reports on clinical trials of severe thrombocytopenia with two different ASO drugs and increased peripheral neuropathy with an siRNA drug, we compared and contrasted the specific safety characteristics of these two classes of oligonucleotide therapeutic. The objectives were to assess factors that could contribute to the specific toxicities observed with these two classes of promising drugs, and get a better understanding of the potential mechanism(s) responsible for these rare, but serious, adverse events.
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Designing a bio-inspired biomimetic in vitro system for the optimization of ex vivo studies of pancreatic cancer ()
Publication date: Available online 30 January 2017 Source:Drug Discovery Today Author(s): Stella Totti, Spyros I. Vernardis, Lisiane Meira, Pedro A. Pérez-Mancera, Eithne Costello, William Greenhalf, Daniel Palmer, John Neoptolemos, Athanasios Mantalaris, Eirini G. Velliou Pancreatic cancer is one of the most aggressive and lethal human malignancies. Drug therapies and radiotherapy are used for treatment as adjuvants to surgery, but outcomes remain disappointing. Advances in tissue engineering suggest that 3D cultures can reflect the in vivo tumor microenvironment and can guarantee a physiological distribution of oxygen, nutrients, and drugs, making them promising low-cost tools for therapy development. Here, we review crucial structural and environmental elements that should be considered for an accurate design of an ex vivo platform for studies of pancreatic cancer. Furthermore, we propose environmental stress response biomarkers as platform readouts for the efficient control and further prediction of the pancreatic cancer response to the environmental and treatment input. Crucial elements for the design of a bio-mimetic bio-inspired tissue engineering platform for pancreatic cancer high throughput drug development and treatment screening are reviewed. Environmental and metabolic stress biomarkers for in situ monitoring of the tumour resistance are proposed.
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Measuring the effectiveness and impact of an open innovation platform ()
Publication date: Available online 27 January 2017 Source:Drug Discovery Today Author(s): Glenn P. Carroll, Sanjay Srivastava, Adam S. Volini, Marta M. Piñeiro-Núñez, Tatiana Vetman Today, most pharmaceutical companies complement their traditional R&D models with some variation on the Open Innovation (OI) approach in an effort to better access global scientific talent, ideas and hypotheses. Traditional performance indicators that measure economic returns from R&D through commercialization are often not applicable to the practical assessment of these OI approaches, particularly within the context of early drug discovery. This leaves OI programs focused on early R&D without a standard assessment framework from which to evaluate overall performance. This paper proposes a practical dashboard for such assessment, encompassing quantitative and qualitative elements, to enable decision-making and improvement of future performance. The use of this dashboard is illustrated using real-time data from the Lilly Open Innovation Drug Discovery (OIDD) program. This article provides a framework for evaluating the effectiveness of the Lilly Open Innovation Drug Discovery program and proposes a global leading indicator dashboard incorporating qualitative and quantitative metrics.
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How can nanoparticles contribute to antituberculosis therapy? ()
Publication date: Available online 27 January 2017 Source:Drug Discovery Today Author(s): Joana Costa-Gouveia, José A. Aínsa, Priscille Brodin, Ainhoa Lucía Therapeutic approaches using nanoparticles are being successfully used in foods and in several fields of medicine, including infectious diseases. Regarding tuberculosis (TB) treatment, nanoparticles can be a useful strategy for two distinct applications: (i) for their intrinsic antimycobacterial activity; (ii) as vehicles for known antitubercular drugs to allow reduction of dose- and drug-associated side-effects and administration via user-friendly administration routes such as pulmonary or oral ones. Promising results were obtained in vitro and in animal Mycobacterium tuberculosis models and need now to be translated into clinical drug candidates. Such a prospect can provide an opportunity regarding the current limited therapeutic options for drug-resistant TB and the scarcity of novel antituberculosis drugs in the drug discovery pipeline.
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Can pharmaceutical co-crystals provide an opportunity to modify the biological properties of drugs? ()
Publication date: Available online 24 January 2017 Source:Drug Discovery Today Author(s): Alessandro Dalpiaz, Barbara Pavan, Valeria Ferretti Poorly soluble and/or permeable molecules jeopardize the discovery and development of innovative medicines. Pharmaceutical co-crystals, formed by an active pharmaceutical substance (API) and a co-crystal former, can show enhanced dissolution and permeation values compared with those of the parent crystalline pure phases. It is currently assumed that co-crystallization with pharmaceutical excipients does not affect the pharmacological activity of an API or, indeed, might even improve physical properties such as solubility and permeability. However, as we highlight here, the biological behavior of co-crystals can differ drastically with respect to that of their parent physical mixtures.
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Models for drug absorption from the small intestine: where are we and where are we going? ()
Publication date: Available online 20 January 2017 Source:Drug Discovery Today Author(s): Pierre-André Billat, Emilie Roger, Sébastien Faure, Frédéric Lagarce The small intestine is a complex organ with movements, flora, mucus and flows. Despite this, the most widely used absorption models consider the organ a cylindrical monoepithelial tube. This review presents the recent evolution of models to take into consideration the complex nature of gut physiology. The most commonly encountered issues are ethical (in vivo models) and differences in drug transport as a result of a modified expression of drug transporters or metabolic enzymes compared with human (in vitro and in vivo models). Finally, this review discusses the way forward to reach an ideal equilibrium between reproducibility, predictability and efficiency for predicting permeability. The features of an ideal model are listed as a guideline for future development. Graphical abstract image We offer a critical analysis of the most widely used absorption models and the current trends in the development of new efficient and relevant models.
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Assessing molecular scaffolds for CNS drug discovery ()
Publication date: Available online 20 January 2017 Source:Drug Discovery Today Author(s): Joan Mayol-Llinàs, Adam Nelson, William Farnaby, Andrew Ayscough There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood–brain barrier. Herein, we demonstrate use of a multiparameter optimisation tool to prioritise the synthesis of molecular scaffolds that, when subsequently decorated, yield screening compounds with experimentally determined properties that align with CNS lead generation needs. Prospective use of this CNS Lead Multiparameter Optimisation (MPO) scoring protocol can guide the further development of novel synthetic methodologies to access CNS-relevant and lead-like chemical space. Graphical abstract image
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The application of principal component analysis to drug discovery and biomedical data ()
Publication date: Available online 19 January 2017 Source:Drug Discovery Today Author(s): Alessandro Giuliani There is a neat distinction between general purpose statistical techniques and quantitative models developed for specific problems. Principal Component Analysis (PCA) blurs this distinction: while being a general purpose statistical technique, it implies a peculiar style of reasoning. PCA is a ‘hypothesis generating’ tool creating a statistical mechanics frame for biological systems modeling without the need for strong a priori theoretical assumptions. This makes PCA of utmost importance for approaching drug discovery by a systemic perspective overcoming too narrow reductionist approaches.
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Therapeutic interventions for aging: the case of cellular senescence ()
Publication date: Available online 19 January 2017 Source:Drug Discovery Today Author(s): Abel Soto-Gamez, Marco Demaria Organismal aging is a multifactorial process characterized by the onset of degenerative conditions and cancer. One of the key drivers of aging is cellular senescence, a state of irreversible growth arrest induced by many pro-tumorigenic stresses. Senescent cells accumulate late in life and at sites of age-related pathologies, where they contribute to disease onset and progression through complex cell and non-cell autonomous effects. Here, we summarize the mechanisms by which cellular senescence can promote aging, and we offer an extensive description of current potential pharmacological interventions for senescent cells, highlighting limitations and suggesting alternatives. Targeting senescent cells offers a new strategy to interfere with morbidities associated with age, and the potential of preventing or delaying aging of multiple tissues.
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