Drug Discovery Today

Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements ()
Publication date: Available online 13 October 2017 Source:Drug Discovery Today Author(s): Francesco Cilurzo, Umberto M. Musazzi, Silvia Franzé, Francesca Selmin, Paola Minghetti Orodispersible dosage forms have a growing presence in the pharmaceutical market because their administration can improve the bioavailability of some drugs and their prescription can ameliorate patient adherence and/or compliance. Here, we review the main features of orodispersible tablets, including oral lyophilisates, and orodispersible films along with their main production technologies. We summarize the bioavailability data and critically discussed their potential to improve patient adherence and/or compliance. We revisit this information in light of both the European Union (EU) and US regulatory frameworks, focusing on the differences in the definitions of such dosage forms and the requirements for marketing authorization. The technological and biopharmaceutical improvements of orodispersible dosage forms are reviewed in the light of regulatory requirements.
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Haspin: a promising target for the design of inhibitors as potent anticancer drugs ()
Publication date: Available online 13 October 2017 Source:Drug Discovery Today Author(s): Nathalie Gisèle Amoussou, André Bigot, Christos Roussakis, Jean-Michel H. Robert Protein kinases constitute a large group of enzymes in eukaryotes and have an important role in many cellular processes. Several of these proteins are active kinases, such as haploid germ cell-specific nuclear protein kinase (Haspin), an atypical eukaryotic protein kinase that lacks sequence similarity with other eukaryotic protein kinases. Haspin is a serine/threonine kinase that associates with chromosome and phosphorylates threonine 3 of histone 3 during mitosis. Haspin overexpression or deletion results in defective mitosis. It has been shown that Haspin inhibitors have potent anti-tumoral effects. Given that the only Haspin substrate is threonine 3 of histone 3, inhibition of Haspin might have fewer adverse effects compared with XXXX. Here, we highlight the chemical structures and actions of currently known Haspin inhibitors. Here, we provide an overview of the chemical structures of described Haspin inhibitors and argue in favour of the relevance of these compounds as a new generation of anticancer drugs.
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Molecular dynamics simulation strategies for designing carbon-nanotube-based targeted drug delivery ()
Publication date: Available online 13 October 2017 Source:Drug Discovery Today Author(s): Mohammed N. Al-Qattan, Pran K. Deb, Rakesh K. Tekade The carbon nanotube (CNT)-based target-specific delivery of drugs, or other molecular cargo, has emerged as one of the most promising biomedical applications of nanotechnology. To achieve efficient CNT-based drug delivery, the interactions between the drug, CNT and biomolecular target need to be properly optimized. Recent advances in the computer-aided molecular design tools, in particular molecular dynamics (MD) simulation studies, offer an appropriate low-cost approach for such optimization. This review highlights the various potential MD approaches for the simulation of CNT interactions with cell membranes while emphasizing various methods of cellular internalization and toxicities of CNTs to build new strategies for designing rational CNT-based targeted drug delivery to circumvent the limitations associated with the various clinically available nonspecific therapeutic agents. Graphical abstract image The carbon-nanotube-based target-specific delivery of drugs, or other molecular cargo, has emerged as one of the most promising biomedical applications of nanotechnology to circumvent the limitations associated with the clinically available various nonspecific therapeutic agents
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Medicinal chemistry in drug discovery in big pharma: past, present and future ()
Publication date: Available online 12 October 2017 Source:Drug Discovery Today Author(s): Ian B. Campbell, Simon J.F. Macdonald, Panayiotis A. Procopiou The changes in synthetic and medicinal chemistry and related drug discovery science as practiced in big pharma over the past few decades are described. These have been predominantly driven by wider changes in society namely the computer, internet and globalisation. Thoughts about the future of medicinal chemistry are also discussed including sharing the risks and costs of drug discovery and the future of outsourcing. The continuing impact of access to substantial computing power and big data, the use of algorithms in data analysis and drug design are also presented. The next generation of medicinal chemists will communicate in ways that reflect social media and the results of constantly being connected to each other and data. What is the future of medicinal chemistry in big pharma? Based on changes from the past to the present, the environment, science and drug discovery paradigm that might be experienced by the medicinal chemist in the future are all explored.
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Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors ()
Publication date: Available online 12 October 2017 Source:Drug Discovery Today Author(s): Mahaveer Singh, Hemant R. Jadhav Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show excellent clinical efficacy for patients with non-small cell lung cancer (NSCLC) with EGFR mutations, including Exon 19 deletion and single-point substitution, and L858R of exon 21. The reason for the reduction in effectiveness of these EGFR TKIs is the T790M gatekeeper mutation in the ATP-binding pocket of Exon 20, which increases the affinity of EGFR for ATP. Newer EGFR TKIs, such as afatinib, osimertinib, rociletinib, EGF816 and ASP8273, selectively target T790M mutants, sparing wild-type EGFR. EGFR TKIs have fewer adverse effects than chemotherapy and also improve progression-free survival. Combination therapy of EGFR TKIs with anti-EGFR antibodies is recommended for overcoming the problem of resistance to some extent. This review could help medicinal chemists to design novel EGFR TKIs against NSCLC. Here, we discuss the structural aspects and development of small-molecule EGFR tyrosine kinase inhibitors to combat the problem of resistance in the treatment of non-small cell lung cancer and to design novel EGFR TKIs.
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Discovery of hidden allosteric sites as novel targets for allosteric drug design ()
Publication date: Available online 10 October 2017 Source:Drug Discovery Today Author(s): Shaoyong Lu, Mingfei Ji, Duan Ni, Jian Zhang Hidden allosteric sites, as a novel type of allosteric site, are invisible in ligand-unbound (apo) crystal structures, but can emerge in ligand-bound (holo) crystal structures when a specific ligand binds to, and stabilizes, a unique conformation favored by the ligand. However, the identification of these sites is a significant challenge. Several computational and experimental approaches have been developed to identify such sites in proteins. Here, we outline these approaches, with a focus on examples of the successful use of such techniques. The discovery of hidden allosteric sites offers a new avenue for facilitating drug design by greatly expanding the repertoire of available drug targets, contributing to the search for allosteric drugs for the treatment of human diseases. Here, we review recent advances in the identification of hidden allosteric sites, with a focus on the successful use of such techniques.
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Demonstrating significant benefit of orphan medicines: analysis of 15 years of experience in Europe ()
Publication date: Available online 9 October 2017 Source:Drug Discovery Today Author(s): Laura Fregonese, Lesley Greene, M. Hofer, Armando Magrelli, Frauke Naumann-Winter, Kristina Larsson, Maria Sheean, Violeta Stoyanova-Beninska, Stelios Tsigkos, Kerstin Westermark, Bruno Sepodes In the European Union demonstration of ‘significant benefit’ is mandatory if satisfactory methods exist for a disease targeted by a new orphan medicinal product. Significant benefit is required at the time of orphan designation, when it can be supported by preclinical studies, and at the time of marketing authorization, when clinical data are needed. For the first time, our work has identified, defined and organized the scientific grounds on which significant benefit is granted in the European Union, based on a review of the orphan medicinal products authorized in the years 2000–2015, and on the working experience of the Committee of Orphan Medicinal Products. The resulting conceptual framework is a tool for medicine developers to reflect on potential areas of advantage of their candidate products, and for a broad range of stakeholders to stimulate the discussion on the added value of orphan medicines across the whole development lifecycle. An analysis of the scientific grounds of the ‘significant benefit’ as per the European Regulation, supporting the added value for patients of those orphan medicinal products that demonstrate to be of significant benefit.
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Phenytoin repositioned in wound healing: clinical experience spanning 60 years ()
Publication date: Available online 6 October 2017 Source:Drug Discovery Today Author(s): Jan M. Keppel Hesselink Drug repositioning is hot, and much development time and money can be spared if one selects an old drug and explores the efficacy and safety in a new indication. Phenytoin is studied and repositioned in many disorders after the initial indication epilepsy (from 1937). Its repositioning in depression was put in the spotlight by the Wall Street icon Jack Dreyfus, already in the 1970s. Innovations in the field of phenytoin still appear to be possible for a number of indications such as wound healing, bipolar disorder and aggression, and via a topical formulation for neuropathic pain. We will discuss wound healing and identified a number of critical issues related to its repositioning in this indication.
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Locked nucleic acid: modality, diversity, and drug discovery ()
Publication date: Available online 6 October 2017 Source:Drug Discovery Today Author(s): Peter H. Hagedorn, Robert Persson, Erik D. Funder, Nanna Albæk, Sanna L. Diemer, Dennis J. Hansen, Marianne R. Møller, Natalia Papargyri, Helle Christiansen, Bo R. Hansen, Henrik F. Hansen, Mads A. Jensen, Troels Koch Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide compound is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties. Locked nucleic acid-modified antisense oligonucleotides (LNAs) are widely used. The structural diversity of LNAs affects most drug properties. Exploiting this diversity offers new opportunities for discovering LNA-based drugs.
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Overcoming or circumventing the stratum corneum barrier for efficient transcutaneous immunization ()
Publication date: Available online 5 October 2017 Source:Drug Discovery Today Author(s): Zhongjian Chen, Yongjiu Lu, Jianping Qi, Quangang Zhu, Yi Lu, Wei Wu Transcutaneous immunization (TCI) is a promising alternative to vaccine delivery via the subcutaneous and intramuscular routes because of the unique immunological characteristics of the skin. However, the stratum corneum (SC) prevents entry of most therapeutic compounds into the body. Several physical devices have been developed to overcome the SC barrier, but still damage the skin. However, by targeting antigens to the abundant perifollicular antigen-presenting cells (APCs), the transfollicular route might be a promising approach for TCI without compromising the skin barrier.
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Relict plastidic metabolic process as a potential therapeutic target ()
Publication date: Available online 5 October 2017 Source:Drug Discovery Today Author(s): Drista Sharma, Rani Soni, Praveen Rai, Bhaskar Sharma, Tarun Kumar Bhatt The alignment of the evolutionary history of parasites with that of plants provides a different panorama in the drug development process. The housing of different metabolic processes, essential for parasite survival, adds to the indispensability of the apicoplast. The different pathways responsible for fueling the apicoplast and parasite offer a myriad of proteins responsible for the apicoplast function. The studies emphasizing the target-based approaches might help in the discovery of antimalarials. The different putative drug targets and their roles are highlighted. In addition, the origin of the apicoplast and metabolic processes are reviewed and the different drugs acting upon the enzymes of the apicoplast are discussed.
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Patient-centered clinical trials ()
Publication date: Available online 4 October 2017 Source:Drug Discovery Today Author(s): Shomesh E. Chaudhuri, Martin P. Ho, Telba Irony, Murray Sheldon, Andrew W. Lo We apply Bayesian decision analysis (BDA) to incorporate patient preferences in the regulatory approval process for new therapies. By assigning weights to type I and type II errors based on patient preferences, the significance level (α) and power (1− β) of a randomized clinical trial (RCT) for a new therapy can be optimized to maximize the value to current and future patients and, consequently, to public health. We find that for weight-loss devices, potentially effective low-risk treatments have optimal αs larger than the traditional one-sided significance level of 5%, whereas potentially less effective and riskier treatments have optimal αs below 5%. Moreover, the optimal RCT design, including trial size, varies with the risk aversion and time-to-access preferences and the medical need of the target population.
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Nonclinical data supporting orphan medicinal product designations: lessons from rare neurological conditions ()
Publication date: Available online 4 October 2017 Source:Drug Discovery Today Author(s): Maria E. Sheean, Violeta Stoyanova-Beninska, Giuseppe Capovilla, Dinah Duarte, Matthias P. Hofer, Michel Hoffmann, Armando Magrelli, Segundo Mariz, Stelios Tsigkos, Evyenia Shaili, Benedetta Polsinelli, Mario Ricciardi, Milton Bonelli, Pavel Balabanov, Kristina Larsson, Bruno Sepodes Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs. This could not only inform future drug development in rare neurological conditions, but also indicate areas where the use of nonclinical models can be made more efficient. This review provides an updated list of animal models that can be used to support orphan designations in rare neurological diseases, and outlines essential features of nonclinical studies that can demonstrate the medical plausibility of a drug.
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HDL functionality in familial hypercholesterolemia: effects of treatment modalities and pharmacological interventions ()
Publication date: Available online 3 October 2017 Source:Drug Discovery Today Author(s): Shiva Ganjali, Amir Abbas Momtazi-Borojeni, Maciej Banach, Petri T. Kovanen, Antonio M. Gotto, Amirhossein Sahebkar Recent studies have demonstrated that assessment of high-density lipoprotein (HDL) functionality indices, instead of HDL cholesterol measurement, is a more robust tool for the evaluation of the functional status of HDL and cardiovascular risk. There are qualitative abnormalities of HDL particles in familial hypercholesterolemia (FH) patients that might represent potential therapeutic targets. Despite the potential promise of optimizing HDL functionality for the treatment of FH, there has been no prior comprehensive review focusing on the impact of different lipid-modifying therapies on HDL functionality in FH patients. In the present review, we aim to fulfill this gap and provide a concise summary on the impact of different lipid-modifying therapies on HDL functionality in FH.
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Carbon nanomaterials in oncology: an expanding horizon ()
Publication date: Available online 28 September 2017 Source:Drug Discovery Today Author(s): Neelesh K. Mehra, Amit K. Jain, Manoj Nahar Carbon nanomaterials have been attracting attention in oncology for the development of safe and effective cancer nanomedicines in increasing improved patient compliance for generally recognized as safe (GRAS) prominence. Toxicity, safety and efficacy of carbon nanomaterials are the major concerns in cancer theranostics. Various parameters such as particle size and shape or surface morphology, surface charge, composition, oxidation and nonoxidative-stress-related mechanisms are prone to toxicity of the carbon nanomaterials. Currently, few cancer-related products have been available on the market, although some are underway in preclinical and clinical phases. Thus, our main aim is to provide comprehensive details on the carbon nanomaterials in oncology from the past two decades for patient compliance and safety.
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Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors ()
Publication date: Available online 22 September 2017 Source:Drug Discovery Today Author(s): Mahalakshmi Ramadoss, Vijayalakshmi Mahadevan Epigenetic and genomic alterations regulate the transcriptional landscape of cells during cancer onset and progression. Recent clinical studies targeting the epigenetic ‘readers’ (bromodomains) for cancer therapy have established the effectiveness of bromodomain (BRD) and extraterminal (BET) inhibitors in treating several types of cancer. In this review, we discuss key mechanisms of BET inhibition and synergistic combinations of BET inhibitors with histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), DNA methyltransferase inhibitors (DNMTi), kinase, B-cell lymphoma 2 (Bcl-2) and proteosome inhibitors, and immunomodulatory drugs for cancer therapy. We also highlight the potential of such combinations to overcome drug resistance, and the evolving approaches to developing novel BET inhibitors. Inhibition of BET Bromodomains has evolved as a promising strategy in cancer therapy. Synergistic combinations involving BET inhibitors and other drugs have proven successful in the clinic and may define new dimensions in epigenetic therapy.
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European regulatory use and impact of subgroup evaluation in marketing authorisation applications ()
Publication date: Available online 21 September 2017 Source:Drug Discovery Today Author(s): Julien Tanniou, Steven Teerenstra, Sagal Hassan, Andre Elferink, Ingeborg van der Tweel, Christine Gispen-de Wied, Kit C.B. Roes Marketing authorisation application dossiers relating to medicinal products containing new active substances and evaluated by the European Medicines Agency (EMA) over the period 2012–2015 were examined. Major objections and other concerns relating to efficacy and safety of the day 80 assessment reports were reviewed. Overall, approved products have more subgroup concerns than nonapproved products, which seems to be a consistent pattern. Subgroup analyses are mainly assessed to have the insurance that subgroups of patients that might lack a positive benefit: risk ratio will not be wrongly included in the approved treatment indication.
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Market entry, power, pharmacokinetics: what makes a successful drug innovation? ()
Publication date: Available online 20 September 2017 Source:Drug Discovery Today Author(s): Susanne Alt, Axel Helmstädter Depending on the timing of market entry, radical innovations can be distinguished from incremental innovations. Whereas a radical innovation typically is the first available derivative of a drug class, incremental innovations are launched later and show a certain benefit compared with the radical innovation. Here, we use historical market data relating to pharmacokinetic (PK), pharmacodynamic (PD), and other drug-related properties to investigate which derivatives within certain drug classes have been most successful on the market. Based on our investigations, we suggest naming the most successful drugs ‘overtaking innovation’, because they often exceed the market share of all the other derivatives. Seven drug classes showed that the overtaking innovation is never a radical innovation, but rather an early incremental innovation, with advantages in manageability and/or tolerance.
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Guiding principles of value creation through collaborative innovation in pharmaceutical research ()
Publication date: Available online 20 September 2017 Source:Drug Discovery Today Author(s): Liang Schweizer, Jeff He Open innovation has become the main trend in pharmaceutical research. Potential obstacles and pitfalls of collaborations often lead to missed opportunities and/or poorly executed partnerships. This paper aims to provide a framework that facilitates the execution of successful collaborations. We start by mapping out three checkpoints onto early-stage collaborative partnerships: inception, ignition and implementation. Different value types and value drivers are then laid out for each phase of the partnership. We proceed to propose a ratio-driven approach and a value-adjustment mechanism, enhancing the probability of successes in pharmaceutical research collaborations. These guiding principles combined should help the partners either reach agreement more quickly or move on to the next potential project.
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Strategies for the enhanced intracellular delivery of nanomaterials ()
Publication date: Available online 15 September 2017 Source:Drug Discovery Today Author(s): Cláudia Azevedo, Maria Helena Macedo, Bruno Sarmento The intracellular delivery of nanomaterials and drugs has been attracting increasing research interest, mainly because of their important effects and functions in several organelles. Targeting specific organelles can help treat or decrease the symptoms of diabetes, cancer, infectious, and autoimmune diseases. Tuning biological and chemical properties enables the creation of functionalized nanomaterials with enhanced intracellular uptake, ability to escape premature lysosome degradation, and to reach a specific target. Here, we provide an update of recent advances in the intracellular delivery mechanisms that could help drugs reach their target more efficiently. This review provides an update of recent advances in intracellular delivery and reports mechanisms that could help drugs reach their target efficiently, resulting in smarter drugs that reach their target still with the original bioavailability.
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Molecular targets and pathways for the treatment of visceral leishmaniasis ()
Publication date: Available online 14 September 2017 Source:Drug Discovery Today Author(s): Vineet Jain, Keerti Jain Visceral leishmaniasis (VL) represents the most severe form of the tropical disease, leishmaniasis. Treatment of VL is complicated because of the few clinically approved antileishmanial drugs available; emerging resistance to first-line drugs; need for a temperature-controlled ‘cold’ supply chain; serious toxicity concerns over drugs such as amphotericin B; high cost of medication; and unavailability of clinically approved antileishmanial vaccines. Attacking potential molecular targets, specific to the parasite, is a vital step in the treatment of this and other infectious diseases. As we discuss here, comprehensive investigation of these targets could provide a promising strategy for the treatment of visceral leishmaniasis.
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Uncovering novel repositioning opportunities using the Open Targets platform ()
Publication date: Available online 14 September 2017 Source:Drug Discovery Today Author(s): Mugdha Khaladkar, Gautier Koscielny, Samiul Hasan, Pankaj Agarwal, Ian Dunham, Deepak Rajpal, Philippe Sanseau The recently developed Open Targets platform consolidates a wide range of comprehensive evidence associating known and potential drug targets with human diseases. We have harnessed the integrated data from this platform for novel drug repositioning opportunities. Our computational workflow systematically mines data from various evidence categories and presents potential repositioning opportunities for drugs that are marketed or being investigated in ongoing human clinical trials, based on evidence strength on target–disease pairing. We classified these novel target–disease opportunities in several ways: (i) number of independent counts of evidence; (ii) broad therapy area of origin; and (iii) repositioning within or across therapy areas. Finally, we elaborate on one example that was identified by this approach.
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Circulatory-cell-mediated nanotherapeutic approaches in disease targeting ()
Publication date: Available online 14 September 2017 Source:Drug Discovery Today Author(s): Thierry Burnouf, Pierre-Alain Burnouf, Yu-Wen Wu, Er-Yuan Chuang, Long-Sheng Lu, Hadi Goubran Circulating blood cells, and cell-derived microvesicles, are emerging as pragmatic delivery systems that can smartly complement the already existing nanotherapeutic platforms evaluated to treat or diagnose diseases. The valuable distinctive features of circulatory cells over synthetic nanocarriers encompass their biological origin which confers immune transparence, known biodegradability, high drug loading, relatively long half-life and a targeting capacity associated with their physiological surface functionality. Absence of nuclei in red blood cells and platelets provides further rationale for their use as cargo vehicles for nucleotoxic agents. Ongoing developments in cell-based and cell-inspired nanotherapies can move drug delivery into reachable frontiers and exhibit high potentiality for translatability into clinical use.
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CHEMGENIE: integration of chemogenomics data for applications in chemical biology ()
Publication date: Available online 14 September 2017 Source:Drug Discovery Today Author(s): Peter S. Kutchukian, Charlie Chang, Sean J. Fox, Erica Cook, Richard Barnard, David Tellers, Huijun Wang, Dante Pertusi, Meir Glick, Robert P. Sheridan, Iain M. Wallace, Anne Mai Wassermann Increasing amounts of biological data are accumulating in the pharmaceutical industry and academic institutions. However, data does not equal actionable information, and guidelines for appropriate data capture, harmonization, integration, mining, and visualization need to be established to fully harness its potential. Here, we describe ongoing efforts at Merck & Co. to structure data in the area of chemogenomics. We are integrating complementary data from both internal and external data sources into one chemogenomics database (Chemical Genetic Interaction Enterprise; CHEMGENIE). Here, we demonstrate how this well-curated database facilitates compound set design, tool compound selection, target deconvolution in phenotypic screening, and predictive model building.
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High-throughput flow cytometry for drug discovery: principles, applications, and case studies ()
Publication date: Available online 12 September 2017 Source:Drug Discovery Today Author(s): Mei Ding, Karin Kaspersson, David Murray, Catherine Bardelle Flow cytometry is a technology providing multiparametric analysis of single cells or other suspension particles. High-throughput (HT) flow cytometry has become an attractive screening platform for drug discovery. In this review, we highlight the recent HT flow cytometry applications, and then focus on HT flow cytometry deployment at AstraZeneca (AZ). Practical considerations for successful HT flow cytometry assay development and screening are provided based on experience from four project case studies at AZ. We provide an overview of the scientific rationale, explain why HT flow cytometry was chosen and how HT flow cytometry assays deliver new ways to support the drug discovery process.
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Near infra red spectroscopy: a tool for solid state characterization ()
Publication date: Available online 8 September 2017 Source:Drug Discovery Today Author(s): Rahul B. Chavan, Nallamothu Bhargavi, Anurag Lodagekar, Nalini R. Shastri Physical characterization of solid form of drug is of paramount importance as its biopharmaceutical properties and/or its processing behavior may be altered. Early identification and monitoring of solid state transformation is a critical requirement for pharmaceutical product development. In combination with chemometrics, a non destructive and non invasive technique like NIR is a powerful tool for solid state characterization. Main focus of this review is application of NIR for qualitative and quantitative analysis of solid forms of drugs and excipients. In addition, this review also sheds light on recent advancement in NIR, such as NIR chemical imaging and NIR based hyphenated techniques.
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Revisiting asthma therapeutics: focus on WNT signal transduction ()
Publication date: Available online 7 September 2017 Source:Drug Discovery Today Author(s): Tim Koopmans, Reinoud Gosens Asthma is a complex disease of the airways that develops as a consequence of both genetic and environmental factors. This interaction has highlighted genes important in early life, particularly those that control lung development, such as the Wingless/Integrase-1 (WNT) signalling pathway. Although aberrant WNT signalling is involved with an array of human conditions, it has received little attention within the context of asthma. Yet it is highly relevant, driving events involved with inflammation, airway remodelling, and airway hyper-responsiveness (AHR). In this review, we revisit asthma therapeutics by examining whether WNT signalling is a valid therapeutic target for asthma. WNT signalling is a relevant, yet underappreciated pathway in asthma. Recent insights into the pathology of asthma have highlighted this pathway as a potential novel therapeutic point of intervention. With this in mind, we attempt to answer the question: is WNT signalling a valid target for asthma therapy?
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Towards carborane-functionalised structures for the treatment of brain cancer ()
Publication date: Available online 5 September 2017 Source:Drug Discovery Today Author(s): Gianpiero Calabrese, Anis Daou, Eugen Barbu, John Tsibouklis Boron neutron capture therapy (BNCT) is a promising targeted chemoradiotherapeutic technique for the management of invasive brain tumors, such as glioblastoma multiforme (GBM). A prerequisite for effective BNCT is the selective targeting of tumour cells with 10B-rich therapeutic moieties. To this end, polyhedral boranes, especially carboranes, have received considerable attention because they combine a high boron content with relative low toxicity and metabolic inertness. Here, we review progress in the molecular design of recently investigated carborane derivatives in light of the widely accepted performance requirements for effective BNCT. The development of carborane derivatives with high cancer-cell targeting specificity is key to these materials fulfilling their promise as the clinical BNCT agents of the future.
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From machine learning to deep learning: progress in machine intelligence for rational drug discovery ()
Publication date: Available online 4 September 2017 Source:Drug Discovery Today Author(s): Lu Zhang, Jianjun Tan, Dan Han, Hao Zhu Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure–activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply. However, when drug discovery moved into the era of ‘big’ data, machine learning approaches evolved into deep learning approaches, which are a more powerful and efficient way to deal with the massive amounts of data generated from modern drug discovery approaches. Here, we summarize the history of machine learning and provide insight into recently developed deep learning approaches and their applications in rational drug discovery. We suggest that this evolution of machine intelligence now provides a guide for early-stage drug design and discovery in the current big data era.
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Contents page 1 ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9
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Contents page 2 ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9
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Therapeutic nanomaterials for cancer therapy and tissue regeneration ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Guorui Jin, Xin Zhao, Feng Xu
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Aggregation-induced emission probes for cancer theranostics ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Meng Gao, Ben Zhong Tang Conventional cancer therapy usually suffers from poor treatment efficiency and adverse effects. To improve the treatment efficiency, it is critical to precisely diagnose specific cancer types and monitor the therapy process in situ. Fluorescence imaging has the advantages of high sensitivity and easy operation, but conventional fluorophores suffer from aggregation-caused quenching (ACQ), and therefore, their applications for imaging or diagnosis are severely impeded. By contrast, aggregation-induced emission (AIE) probes have significant advantages in terms of excellent photostability and a lack of self-quenching, and can be conveniently incorporated into theranostic platforms by combining them with various therapeutic modalities. Here, we discuss and summarize the recent advances in the development of AIE probes for cancer theranostics.
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Nanoparticles for immune system targeting ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Juan Du, Yu Shrike Zhang, Divia Hobson, Per Hydbring Nanoparticles (NPs) are found in numerous applications used to modulate the immune system. They serve as drug delivery carriers or vaccine adjuvants and are utilized as therapeutics against a variety of diseases. NPs can be engineered to target distinct cellular components representing multiple pathways of immunity. The combination of NPs with immune system-targeting moieties has paved the way for improved targeted immune therapies. Here we provide an update of recent progress in this field.
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Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Hong Zhao, Ruihua Ding, Xin Zhao, Yiwei Li, Liangliang Qu, Hao Pei, Lara Yildirimer, Zhengwei Wu, Weixia Zhang Here, we discuss the biomedical applications of graphene-based nanomaterials (GBNs). We examine graphene and its various derivatives, including graphene, graphene oxides (GOs), reduced graphene oxides (rGOs), graphene quantum dots (GQDs), and graphene composites, and discuss their unique properties related to their biomedical applications. We also summarize the detailed biomedical applications of GBNs, including drug and/or gene delivery, bioimaging, and tissue engineering. We also highlight the toxicity of these nanomaterials.
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Recent development of synthetic nonviral systems for sustained gene delivery ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Yonggang Xiang, Nwe Nwe Linn Oo, Jin Ping Lee, Zibiao Li, Xian Jun Loh Sustained gene delivery is of particular importance today because it circumvents the need for repeated therapeutic administration and provides spatial and temporal control of the release profile. Better understanding of the genetic basis of diseases and advances in gene therapy have propelled significant research on biocompatible gene carriers for therapeutic purposes. Varied biodegradable polymer-based architectures have been used to create new compositions with unique properties suitable for sustained gene delivery. This review presents the most recent advances in various polymeric systems: hydrogels, microspheres, nanospheres and scaffolds, having complex architectures to encapsulate and deliver functional genes. Through the recombination of different existing polymer systems, the multicomplex systems can be further endowed with new properties for better-targeted biomedical applications.
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Development of nanomaterials for bone-targeted drug delivery ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Hao Cheng, Aditya Chawla, Yafeng Yang, Yuxiao Li, Jin Zhang, Hae Lin Jang, Ali Khademhosseini Bone is one of the major organs of the human body; it supports and protects other organs, produces blood cells, stores minerals, and regulates hormones. Therefore, disorders in bone can cause serious morbidity, complications, or mortality of patients. However, despite the significant occurrence of bone diseases, such as osteoarthritis (OA), osteoporosis (OP), non-union bone defects, bone cancer, and myeloma-related bone disease, their effective treatments remain a challenge. In this review, we highlight recent progress in the development of nanotechnology-based drug delivery for bone treatment, based on its improved delivery efficiency and safety. We summarize the most commonly used nanomaterials for bone drug delivery. We then discuss the targeting strategies of these nanomaterials to the diseased sites of bone tissue. We also highlight nanotechnology-based drug delivery to bone cells and subcellular organelles. We envision that nanotechnology-based drug delivery will serve as a powerful tool for developing treatments for currently incurable bone diseases.
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Electrospun polymeric micro/nanofibrous scaffolds for long-term drug release and their biomedical applications ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Qiang Zhang, Yingchun Li, Zhi Yuan (William) Lin, Kenneth K.Y. Wong, Min Lin, Lara Yildirimer, Xin Zhao Electrospun polymeric micro/nanofibrous scaffolds have been investigated extensively as drug delivery platforms capable of controlled and sustained release of therapeutic agents in situ. Such scaffolds exhibit excellent physicochemical and biological properties and can encapsulate and release various drugs in a controlled fashion. This article reviews recent advances in the design and manufacture of electrospun scaffolds for long-term drug release, placing particular emphasis on polymer selection, types of incorporated drugs and the latest drug-loading techniques. Finally, applications of such devices in traumatic or disease states requiring effective and sustained drug action are discussed and critically appraised in their biomedical context. Electrospun polymeric fibrous scaffolds with excellent physicochemical and biological properties offer great flexibility to encapsulate and release various drugs for a long term, with great potential to repair damaged or diseased tissues.
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Recent advances in activatable fluorescence imaging probes for tumor imaging ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Jing Zhao, Guorui Jin, Guojun Weng, Jianjun Li, Jian Zhu, Junwu Zhao Fluorescence imaging is superior in sensitivity and resolution compared with other imaging modalities; however, its application is hindered by high background noise. Tissue-selective strategies, such as passive, active, and activatable targeting, hold great promise in accelerating clinical translation by significantly improving the tumor:background ratio (TBR) and, in turn, the sensitivity and contrast of fluorescence imaging. Compared with the ‘always on’ contrast agents, activatable probes, which remain nonfluorescent until being activated by tumor-specific molecular targets, further enhance TBR and at the same time provide additional molecular information that can be related to tumor staging and therapy response. In this review, we summarize recent advances in the development of activatable fluorescence probes and provide insights into their advantages and limitations when used for tumor imaging.
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Biomimetic nanofibrous scaffolds for neural tissue engineering and drug development ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Jing Wu, Lili Xie, William Zhi Yuan Lin, Qiushui Chen Neural tissue engineering aims to develop functional substitutes for damaged tissues, creating many promising opportunities in regeneration medicine and drug discovery. Biomaterial scaffolds routinely provide nerve cells with a physical support for cell growth and regeneration, yielding 3D extracellular matrix to mimic the in vivo cellular microenvironment. Among the various types of cellular scaffolds for reconstruction, biomimetic nanofibrous scaffolds are recognized as appropriate candidates by precisely controlling morphology and shape. Here, we review the current techniques in fabricating biomimetic nanofibrous scaffolds for neural tissue engineering, and describe the impact of nanofiber components on the properties of scaffolds and their uses in therapeutic models and drug development. We also discuss the current challenges and future directions of applying 3D printing and microfluidic technologies in neural tissue engineering.
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Nanomaterial scaffolds to regenerate musculoskeletal tissue: signals from within for neovessel formation ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Zuyong Wang, Feng Wen, Poon Nian Lim, Qinyuan Zhang, Toshiisa Konishi, Dong Wang, Swee Hin Teoh, Eng San Thian Current treatments for musculoskeletal disease and injury are restricted with the usage of autografts and allografts. Tissue engineering that applies the principles of biology and engineering to develop functional substitutes has potential promise of therapeutic regeneration for musculoskeletal tissues. However, engineering sizable tissues needs a vascular network to supply cells with nutrients, oxygen and signals after implantation. For this purpose, recent developments on therapeutic nanomaterials have been explored in delivering different vessel-inductive growth factors, small biomolecules and ions for scalable engineering into vascularizable scaffolds. Here, we provide an overview on the current efforts, and propose future perspectives for precise regulation on vascularization processes and musculoskeletal tissue functionality.
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Cancer-on-a-chip systems at the frontier of nanomedicine ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Yu Shrike Zhang, Yi-Nan Zhang, Weijia Zhang Nanomedicine provides a unique opportunity for promoting drug efficacy through enhanced delivery mechanisms. However, its translation into the clinics has been relatively slow compared with the large amount of research occurring in laboratory settings. Given the limitations of conventional cell culture models and preclinical animal models, we discuss the potential utility of recently developed cancer-on-a-chip platforms, which maximally replicate the pathophysiology of the human tumor microenvironments, as alternatives for effective evaluation of nanomedicine. We begin with a brief discussion of nanomedicine, then chart the history of organ-on-a-chip platform development and their recent evolution as tools for modeling different cancers for assessing nanomedicine efficacy, concluding with future perspectives for the field.
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Bioimaging and biodetection assisted with TTA-UC materials ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Qingqing Dou, Lu Jiang, Dan Kai, Cally Owh, Xian Jun Loh Upconversion of light has attracted intensive studies for biomedical research, because it enables deeper tissue analysis owing to the longer wavelength of incident light, compared with conventional downconversion fluorescent materials. Triplet–triplet annihilation (TTA), as a typical mechanism of upconversion, does not necessitate high power excitation and exhibits a higher quantum yield than rare earth upconversion owing to more sensitizer options with higher absorption coefficients. A desirable wavelength range of excitation and emission can be realized by careful selection of the combination of sensitizer and activator. Therefore, TTA-UC is worth exploring further for biorelated applications, such as bioimaging and biodetection. Recent developments are reviewed in this article.
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In vivo cancer research using aggregation-induced emission organic nanoparticles ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Xiaoyong Yi, Jun Li, Zhipeng Zhu, Qian Liu, Qiang Xue, Dan Ding Exploration of a nanoplatform that benefits precise cancer diagnosis and treatment in vivo is particularly valuable. In recent years, aggregation-induced emission luminogens (AIEgens) have emerged as advanced fluorescent materials for the design and preparation of organic nanoparticles (NPs); they also have unique advantages in biomedical applications, especially in cancer diagnosis and theranostics. In this review, we summarize the current status of the development of AIEgen-based NPs for in vivo cancer research, including in vivo tumor diagnosis, drug delivery, and photodynamic therapy. We hope that our review will inspire more exciting research in cross-disciplinary fields, contributing to precise cancer diagnostics and therapeutics.
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Next-generation superparamagnetic iron oxide nanoparticles for cancer theranostics ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Kai Li, Hossein Nejadnik, Heike E. Daldrup-Link Superparamagnetic iron oxide (SPIO) nanoparticles have been intensively studied for the development of contrast agents in MRI. First-generation SPIO nanoparticles had diagnostic capabilities only, whereas a new generation of SPIO nanoparticle has multifunctional characteristics for combined therapeutic and diagnostic applications. These theranostic nanoparticles hold great potential for image-guided cancer therapies. In particular, polymer-coated theranostic SPIO nanoparticles have enjoyed increasing attention as a result of good biocompatibility, biodegradability and versatile functionality endowed by polymeric matrices. This review provides an overview of recently developed polymer-coated multifunctional SPIO nanoparticles for cancer theranostics and discusses current challenges and future perspectives.
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Carbon nanomaterials as versatile platforms for theranostic applications ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Mirae Kim, Jinhyeong Jang, Chaenyung Cha Theranostic nanomedicine, utilizing state-of-the-art, multifaceted nanomaterials and devices with therapeutic and diagnostic dual functions, has emerged as a highly attractive and promising new field of medicine. The theory behind the use of nanomaterials for theranostic applications is to impart multifunctionality by applying various engineering strategies to combine different modalities on a nanoscale. Carbon nanomaterials, which have been a subject of intense scientific research and industrial applications in recent years, have also found their way into theranostic nanomedicine owing to their innate multifunctionality. In this review, we outline recent research progress and trends in utilizing various types of carbon nanomaterial for theranostic applications.
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Engineered nanoparticles for the detection, treatment and prevention of atherosclerosis: how close are we? ()
Publication date: September 2017 Source:Drug Discovery Today, Volume 22, Issue 9 Author(s): Luong T.H. Nguyen, Aristo Muktabar, Jinkai Tang, Vinayak P. Dravid, C. Shad Thaxton, Subbu Venkatraman, Kee Woei Ng Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. Nanotechnology has provided the possibility of designing nanoparticles that can translocate through tissues and home in to atherosclerotic plaques to achieve desired diagnostic, therapeutic, theranostic or ‘theralivery’ outcomes. Although nanomedicine approaches have demonstrated exciting possibilities, clinical reality is still distant and challenges are aplenty, such as specificity of targeting and nanotoxicity. Nevertheless, developments in formulations, delivery strategies and experimental models over the coming years will generate new knowledge to define the true potential of this field. This review discusses the most recent developments, current challenges and future possibilities.
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Finding hidden treasures in old drugs: the challenges and importance of licensing generics ()
Publication date: Available online 1 September 2017 Source:Drug Discovery Today Author(s): Melek Simsek, Berrie Meijer, Adriaan A. van Bodegraven, Nanne K.H. de Boer, Chris J.J. Mulder Identifying new indications for existing drugs creates new therapeutic options while bypassing much of the costs and time involved with bringing a new drug to market. The rediscovery of a generic drug, however, is a challenging pursuit because there is no formal regulatory approach and a lack of economic interest by pharmaceutical companies. This played a part in the re-registration of thioguanine as a rescue drug for the treatment of patients with inflammatory bowel disease in The Netherlands. In this article, we aim to underline the importance of drug rediscovery, the difficulties of this procedure in Europe and we attempt to suggest conceivable solutions.
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Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca–Charles River Laboratories strategic relationship ()
Publication date: Available online 26 August 2017 Source:Drug Discovery Today Author(s): Frederic D.C. Martin, Amanda Benjamin, Ruth MacLean, David M. Hollinshead, Claire Landqvist In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies.
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RanBPM: a potential therapeutic target for modulating diverse physiological disorders ()
Publication date: Available online 26 August 2017 Source:Drug Discovery Today Author(s): Soumyadip Das, Bharathi Suresh, Hyongbum (Henry) Kim, Suresh Ramakrishna The Ran-binding protein microtubule-organizing center (RanBPM) is a highly conserved nucleocytoplasmic protein involved in a variety of intracellular signaling pathways that control diverse cellular functions. RanBPM interacts with proteins that are linked to various diseases, including Alzheimer’s disease (AD), schizophrenia (SCZ), and cancer. In this article, we define the characteristics of the scaffolding protein RanBPM and focus on its interaction partners in diverse physiological disorders, such as neurological diseases, fertility disorders, and cancer.
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