Drug Discovery Today

Pharmaceutical nanocrystals: production by wet milling and applications ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Maria Malamatari, Kevin M.G. Taylor, Stavros Malamataris, Dennis Douroumis, Kyriakos Kachrimanis Nanocrystals are regarded as an important nanoformulation approach exhibiting advantages of increased dissolution and saturation solubility with chemical stability and low toxicity. Nanocrystals are produced in the form of nanosuspensions using top-down (e.g., wet milling or high pressure homogenization) and bottom-up methods (e.g., antisolvent precipitation). Wet milling is a scalable method applicable to drugs with different physicochemical and mechanical properties. Nanocrystalline-based formulations, either as liquid nanosuspensions or after downstream processing to solid dosage forms, have been developed as drug delivery systems for various routes of administration (i.e., oral, parenteral, pulmonary, ocular, and dermal). In this review, we summarize and discuss the features, preparation methods, and therapeutic applications of pharmaceutical nanocrystals, highlighting their universality as a formulation approach for poorly soluble drugs. This review outlines the advantages, stabilization, and production of drug nanocrystals with an emphasis on wet milling. Covering their pharmaceutical applications, it reveals why nanocrystals are an industrially feasible formulation strategy.
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Light-triggerable formulations for the intracellular controlled release of biomolecules ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Miguel M. Lino, Lino Ferreira New therapies based on the use of biomolecules [e.g., proteins, peptides, and non-coding (nc)RNAs] have emerged during the past few years. Given their instability, adverse effects, and limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. Sophisticated nanoformulations responsive to light offer an excellent opportunity for the controlled release of these biomolecules, enabling the control of timing, duration, location, and dosage. In this review, we discuss the design principles for the delivery of biomolecules, in particular proteins and RNA-based therapeutics, by light-triggerable formulations. We further discuss the opportunities offered by these formulations in terms of endosomal escape, as well as their limitations. Increasing numbers of proteins and noncoding RNAs are being described as new therapeutic agents. The controlled release of these biomolecules could offer opportunities in the context of several biomedical applications.
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Unlocking the full potential of open innovation in the life sciences through a classification system ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Niclas Nilsson, Timo Minssen A common understanding of expectations and requirements is critical for boosting research-driven business opportunities in open innovation (OI) settings. Transparent communication requires common definitions and standards for OI to align the expectations of both parties. Here, we suggest a five-level classification system for OI models, reflecting the degree of openness. The aim of this classification system is to reduce contract negotiation complexity and times between two parties looking to engage in OI. Systematizing definitions and contractual terms for OI in the life sciences helps to reduce entry barriers and boosts collaborative value generation. By providing a contractual framework with predefined rules, science will be allowed to move more freely, thus maximizing the potential of OI. Here we discuss a new classification system that suggests a clear definition to what ‘open’ in fact means in collaborative research. Better-aligned expectations will reduce the negotiation complexity and increase focus on exploring science under the open innovation banner.
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Phage-derived lysins as potential agents for eradicating biofilms and persisters ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Umender Sharma, Aradhana Vipra, Shankaramurthy Channabasappa Bacterial biofilms are highly resistant to the action of antibiotics. Presence of persisters, phenotypically resistant populations of bacterial cells, is thought to contribute toward recalcitrance of biofilms. The phage-derived lysins, by virtue of their ability to cleave the peptidoglycan of bacterial cells in an enzymatic manner, have the unique ability to kill dormant cells. Several lysins have shown potent antibiofilm activity in vitro. The fact that lysins have shown better efficacy than conventional drugs in animal models of endocarditis and other infections involving biofilms suggests that the lysins can potentially be developed against difficult-to-treat bacterial infections. Phage lysins, because of their excellent antibiofilm and antipersister properties, are emerging as strong candidates for developing therapies for difficult-to-treat chronic and recurrent bacterial infections.
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NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Nunzio Iraci, Oriana Tabarrini, Claudio Santi, Luca Sancineto Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies. Around 20 years of drug discovery campaigns devoted to the identification of NCp7 noncovalent inhibitors are exhaustively reviewed to provide fruitful insights for future drug discovery.
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Overcoming the resistance mechanisms of Smoothened inhibitors ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Xiaochun Dong, Chenglin Wang, Zhongjian Chen, Weili Zhao Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors. How should we deal with the emergency of mutation-related resistance during treatment with marketed Smo inhibitors? A better understanding of resistance mechanisms is essential for improving therapeutic strategies to obtain durable responses to such targeted therapies.
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Ligandomics: a paradigm shift in biological drug discovery ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Wei Li, Iok-Hou Pang, Mario Thiego F. Pacheco, Hong Tian As productivity of pharmaceutical research and development (R&D) for small-molecule drugs declines, the trend in drug discovery strategies is shifting towards biologics, which predominantly target secreted or cell surface proteins. Receptors and ligands are the most-valuable drug targets. In contrast to conventional approaches of discovering one ligand at a time, the emerging technology of ligandomics can systematically map disease-selective cellular ligands in the absence of molecular probes. Biologics targeting these ligands with disease selectivity have the advantages of high efficacy, minimal adverse effects, wide therapeutic indices, and low safety-related attrition rates. Therefore, ligandomics represents a paradigm shift to address the bottleneck of target discovery for biologics development. Graphical abstract image
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Macromolecule nanotherapeutics: approaches and challenges ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Puneet Tyagi, Jose Luis Santos With the advent of technology, newer forms of drugs, such as proteins, DNA, and RNA, have entered mainstream product development. However, systemic delivery of macromolecules is limited by rapid blood clearance, poor stability in vivo, and inadequate uptake by cells. Nanoparticle (NP)-based delivery systems have emerged as suitable carriers for overcoming such pharmacokinetic limitations of macromolecule delivery. Nanocarriers, such as liposomes, provide protection for sensitive drug materials and also enhance the circulation half-life of=therapeutics. Nanocarriers have also been shown to promote cellular uptake and the release of intact macromolecules in the cell. Besides liposomes, other nanocarriers, such as gold and iron oxide NPs, are also now being tested in clinical trials. Graphical abstract image Recent trends in disease treatment have changed from traditional medications and targeted therapies towards harnessing the immune system to fight the disease. This has suggested a novel approach for the utility of nanocarriers. Furthermore, nanocarriers are being used for parenteral gene delivery, for which, until recently, only viral vectors were being evaluated. Here, we provide an update on nanocarriers that have been tested in the clinic and the challenges to the development of such nanocarriers.
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Mechanism of nanoparticle-induced hypersensitivity in pigs: complement or not complement? ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): János Szebeni A recent study on nanoparticle-induced hypersensitivity reactions in pigs showed robust pulmonary intravascular macrophage clearance of Polybead® carboxylate microspheres in mediating the adverse cardiopulmonary distress, irrespective of the ability of these particles to activate the Complement (C) system in vitro. Focusing on this observation, this article highlights the controversies in projecting in vitro C assay data to in vivo conditions and applying data on polystyrene particles to therapeutic nanopharmaceuticals. Based on overwhelming evidence of a role of anaphylatoxins in hypersensitivity reactions, the need to further explore the role of C activation in the reported and other reactions is highlighted. C-activation-related and C-independent pseudoallergies (CARPA and CIPA) can proceed simultaneously, as outlined by the ‘double-hit’ hypothesis. The role of complement activation in hypersensitivity reactions to nanoparticle-based drugs has been questioned by in vitro data. This review questions the relevance of these data and suggests that complement-dependent and −independent mechanisms can be reconciled under the ‘double-hit’ theory.
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Use of CRISPR/Cas9 gene-editing tools for developing models in drug discovery ()
Publication date: Available online 8 January 2018 Source:Drug Discovery Today Author(s): Gulzar Ahmad, Mansoor Amiji Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9 (CRISPR/Cas9) enables targeted genome engineering. The simplicity of this system, its facile engineering, and amenability to multiplex genes make it the system of choice for many applications. This system has revolutionized our ability to carry out gene editing, transcription regulation, genome imaging, and epigenetic modification. In this review, we discuss the discovery of CRISPR/Cas9, its mechanism of action, its application in medicine and animal model development, and its delivery. We also highlight how the CRISPR/Cas9 system can affect the next generation of drugs by accelerating the identification and validation of high-value targets. The generation of precision disease models through this system will provide a rapid avenue for functional drug screening. XXXX.
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From clinical proof-of-concept to commercialization of CAR T cells ()
Publication date: Available online 6 January 2018 Source:Drug Discovery Today Author(s): Boris Calmels, Bechara Mfarrej, Christian Chabannon The development of CAR T cells currently represents an exciting opportunity to convert the already published clinical successes observed in clinical trials into commercially available efficient therapies. However, the path toward successful commercialization is still hindered by many hurdles. Here, we review such issues as: the need for structured collaborations between hospital collection and clinical facilities and industry manufacturing facilities to streamline the supply chain; necessity for uniform and efficient medical procedures to cope with severe toxicities associated with CAR T cells; and absolute need to define an economical and sustainable model for manufacturers and payers. The fast pace at which the field is evolving requires careful assessments for the benefit of patients. Several challenges are yet to be met before successful commercialization of CAR T cells including: scientific, manufacturing and regulatory assessments.
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Astrocytes as targets for drug discovery ()
Publication date: Available online 6 January 2018 Source:Drug Discovery Today Author(s): Kirill Gorshkov, Francis Aguisanda, Natasha Thorne, Wei Zheng Recent studies have illuminated the crucial role of astrocytes in maintaining proper neuronal health and function. Abnormalities in astrocytic functions have now been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Historically, drug development programs for neurodegenerative diseases generally target only neurons, overlooking the contributions of astrocytes. Therefore, targeting both disease neurons and astrocytes offers a new approach for drug development for the treatment of neurological diseases. Looking forward, the co-culturing of human neurons with astrocytes could be the next evolutionary step in drug discovery for neurodegenerative diseases.
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The microRNA landscape of cutaneous squamous cell carcinoma ()
Publication date: Available online 6 January 2018 Source:Drug Discovery Today Author(s): Kathryn Konicke, Argelia Lopez, José Luis Muñoz, Luis Steven Servin, Armando Flores, Edit Olasz, Zelmira Lazarova Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived skin tumor. It is the second-most-common cancer affecting the Caucasian population and is responsible for >20% of all skin-cancer-related deaths. The estimated incidence of non-melanoma skin cancer in the USA is >1000000 cases per year, of which roughly 20–30% are squamous cell carcinoma. To better understand and treat this challenging cancer, current research focuses on development of novel strategies to improve the understanding of tumor biogenesis on an individual basis. microRNAs are becoming important biomarkers in the diagnosis, prognosis and treatment of cSCC. This review describes the current knowledge on miRNA expression in cSCC and its role as a biomarker for personalized medicine.
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Administration of antioxidants in cancer: debate of the decade ()
Publication date: Available online 6 January 2018 Source:Drug Discovery Today Author(s): Rajneet Kaur Khurana, Ashay Jain, Atul Jain, Teenu Sharma, Bhupinder Singh, Prashant Kesharwani Several randomized clinical trials have divulged that administration of antioxidants during chemotherapy decreases the effectiveness of treatment. Hence, the characteristic feature of this article is extensive assessment of putative benefits and potential risks of natural and synthetic antioxidant supplementation, administered with chemotherapy, based upon the available preclinical and clinical data. After analyzing mixed results, it was concluded that current FDA guidelines should be followed before supplementing antioxidants during cytotoxic treatment. Nevertheless, contradictory experimental animal models opposing human clinical trials discourage the concurrent administration of antioxidants ostensibly owing to the possibility of tumor protection and reduced survival.
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Corrigendum to “Amyloid beta modulators and neuroprotection in Alzheimer’s disease: a critical appraisal” [Drug Discov. Today 22 (February (2)) (2017) 223–233] ()
Publication date: Available online 5 January 2018 Source:Drug Discovery Today Author(s): Chandra Sekhar Kuruva, P. Hemachandra Reddy
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Corrigendum to “Bispecific antibodies” [Drug Discov. Today 20 (July (7)) (2015) 838–847] ()
Publication date: Available online 5 January 2018 Source:Drug Discovery Today Author(s): Roland E. Kontermann, Ulrich Brinkmann
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Real world big data for clinical research and drug development ()
Publication date: Available online 30 December 2017 Source:Drug Discovery Today Author(s): Gurparkash Singh, Duane Schulthess, Nigel Hughes, Bart Vannieuwenhuyse, Dipak Kalra The objective of this paper is to identify the extent to which real world data (RWD) is being utilized, or could be utilized, at scale in drug development. Through screening peer-reviewed literature, we have cited specific examples where RWD can be used for biomarker discovery or validation, gaining a new understanding of a disease or disease associations, discovering new markers for patient stratification and targeted therapies, new markers for identifying persons with a disease, and pharmacovigilance. None of the papers meeting our criteria was specifically geared toward new novel targets or indications in the biopharmaceutical sector; the majority were focused on the area of public health, often sponsored by universities, insurance providers or in combination with public health bodies such as national insurers. The field is still in an early phase of practical application, and is being harnessed broadly where it serves the most direct need in public health applications in early, rare and novel disease incidents. However, these exemplars provide a valuable contribution to insights on the use of RWD to create novel, faster and less invasive approaches to advance disease understanding and biomarker discovery. We believe that pharma needs to invest in making better use of EHRs and the need for more precompetitive collaboration to grow the scale of this ‘big denominator’ capability, especially given the needs of precision medicine research.
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Pathway-based technologies for early drug discovery ()
Publication date: Available online 30 December 2017 Source:Drug Discovery Today Author(s): Chris Fotis, Asier Antoranz, Dimitris Hatziavramidis, Theodore Sakellaropoulos, Leonidas G. Alexopoulos Although the traditional drug discovery approach has led to the development of many successful drugs, the attrition rates remain high. Recent advances in systems-oriented approaches (systems-biology and/or pharmacology) and ‘omics technologies has led to a plethora of new computational tools that promise to enable a more-informed and successful implementation of the reductionist, one drug for one target for one disease, approach. These tools, based on biomolecular pathways and interaction networks, offer a systematic approach to unravel the mechanism(s) of a disease and link them to the chemical space and network footprint of a drug. Drug discovery can draw upon this holistic approach to identify the most-promising targets and compounds during the early phases of development. Graphical abstract image
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Contents page 1 ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12
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Contents page 2 ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12
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Do large mergers increase or decrease the productivity of pharmaceutical R&D? ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 Author(s): Michael S. Ringel, Michael K. Choy There is current uncertainty regarding the effects of mergers on pharmaceutical R&D productivity, with various mechanisms reported by which mergers could either help or harm R&D, and mixed empirical findings in prior analyses. Here, we present an analysis that is novel in several ways: we use downstream measures of R&D productivity, account for both inputs and outputs in our calculations, and use a self-controlled design. We find that recent large pharmaceutical mergers are associated with statistically significant increases in R&D productivity. These results are perhaps not surprising in light of the broader literature on R&D productivity that points to two factors as instrumental in driving higher R&D productivity (depth of scientific information, and objectivity of decision-making based on that information), both of which could be expected to increase because of a merger.
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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: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 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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European regulatory use and impact of subgroup evaluation in marketing authorisation applications ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 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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Tocotrienols: the unsaturated sidekick shifting new paradigms in vitamin E therapeutics ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 Author(s): Madhu M. Kanchi, Muthu K. Shanmugam, Grishma Rane, Gautam Sethi, Alan P. Kumar Vitamin E family members: tocotrienols and tocopherols are widely known for their health benefits. Decades of research on tocotrienols have shown they have diverse biological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also modulate several intracellular molecular targets and, most importantly, have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials. This review provides a comprehensive update on the little-known therapeutic potentials of tocotrienols, which tocopherols lack in a variety of inflammation-driven diseases. Vitamin E is a lipid-soluble, radical buster existing in two different isoforms: tocotrienols and tocopherols, and has been used continuously because of its many biological activities, which are pharmacologically capable of tackling a wide array of diseases, thus improving health issues occurring every day.
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Polypharmacology of conformationally locked methanocarba nucleosides ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 Author(s): Kenneth A. Jacobson, Dilip K. Tosh, Kiran S. Toti, Antonella Ciancetta A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds. Graphical abstract image The scope of action of nucleosides, widely used anticancer and antiviral drugs, is now extended to unconventional targets, including diverse receptors, enzymes and transporters, using a conformational lock.
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Structural coverage of the proteome for pharmaceutical applications ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 Author(s): Joseph C. Somody, Stephen S. MacKinnon, Andreas Windemuth Structure-based computational drug discovery efforts have traditionally focused on the structure of a single, well-known drug target. Important applications, such as target deconvolution and the analysis of polypharmacology, require proteome-scale molecular docking and have been inaccessible to structure-based in silico approaches. One important reason for this inaccessibility was that the structure of most proteins was not known. Lately, this ‘structure gap’ has been closing rapidly, and proteome-scale molecular docking seems within reach. Here, we survey the current state of structural coverage of the human genome and find that coverage is truly proteome-wide, both overall and in most pharmaceutically relevant categories of proteins. The time is right for structure-based approaches to target deconvolution and polypharmacology.
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Uncovering novel repositioning opportunities using the Open Targets platform ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 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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Label-free technology and patient cells: from early drug development to precision medicine ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 Author(s): Julia M. Hillger, Wai-Ling Lieuw, Laura H. Heitman, Adriaan P. IJzerman Drug development requires physiologically more appropriate model systems and assays to increase understanding of drug action and pathological processes in individual humans. Specifically, patient-derived cells offer great opportunities as representative cellular model systems. Moreover, with novel label-free cellular assays, it is often possible to investigate complex biological processes in their native environment. Combining these two offers distinct opportunities for increasing physiological relevance. Here, we review impedance-based label-free technologies in the context of patient samples, focusing on commonly used cell types, including fibroblasts, blood components, and stem cells. Applications extend as far as tissue-on-a-chip models. Thus, applying label-free technologies to patient samples can produce highly biorelevant data and, with them, unique opportunities for drug development and precision medicine. Graphical abstract image
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RanBPM: a potential therapeutic target for modulating diverse physiological disorders ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 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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Zinc oxide nanoparticles: a promising nanomaterial for biomedical applications ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 Author(s): Pawan K. Mishra, Harshita Mishra, Adam Ekielski, Sushama Talegaonkar, Bhuvaneshwar Vaidya Zinc oxide (ZnO) nanoparticles (NPs) are a promising platform for use in biomedical research, especially given their anticancer and antimicrobial activities. These activities are associated with the ability of ZnO NPs to generate reactive oxygen species (ROS) and induce apoptosis. In addition, ZnO NPs have been successfully exploited as drug carriers for loading and transporting drugs to target sites, thereby reducing unwanted toxicity and off-target effects, and resulting in amplified synergistic effects. Here, we discuss the synthesis and biomedical applications of ZnO NPs.
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Near infra red spectroscopy: a tool for solid state characterization ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 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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High-throughput flow cytometry for drug discovery: principles, applications, and case studies ()
Publication date: December 2017 Source:Drug Discovery Today, Volume 22, Issue 12 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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One-size-fits-all dosing in oncology wastes money, innovation and lives ()
Publication date: Available online 21 November 2017 Source:Drug Discovery Today Author(s): David C. Norris
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Understanding missing proteins: a functional perspective ()
Publication date: Available online 20 November 2017 Source:Drug Discovery Today Author(s): Longjian Zhou, Limsoon Wong, Wilson Wen Bin Goh A missing protein (MP) is an unconfirmed genetic sequence for which a protein product is not yet detected. Currently, MPs are tiered based on supporting evidence mainly in the form of protein existence (PE) classification. As we discuss here, this definition is overly restrictive because proteins go missing in day-to-day proteomics as a result of low abundance, lack of sequence specificity, splice variants, and so on. Thus, we propose a broader functional classification of MPs that complements PE classification, discuss major causes, and examine three corresponding solution tiers: biological, technical, and informatics. We assert that informatics-driven solutions would have a major role in resolving the MP problem (MPP).
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Recent advances in bacteriophage-based methods for bacteria detection ()
Publication date: Available online 20 November 2017 Source:Drug Discovery Today Author(s): Łukasz Richter, Marta Janczuk-Richter, Joanna Niedziółka-Jönsson, Jan Paczesny, Robert Hołyst Fast and reliable bacteria detection is crucial for lowering the socioeconomic burden related to bacterial infections (e.g., in healthcare, industry or security). Bacteriophages (i.e., viruses with bacterial hosts) pose advantages such as great specificity, robustness, toughness and cheap preparation, making them popular biorecognition elements in biosensors and other assays for bacteria detection. There are several possible designs of bacteriophage-based biosensors. Here, we focus on developments based on whole virions as recognition agents. We divide the review into sections dealing with phage lysis as an analytical signal, phages as capturing elements in assays and phage-based sensing layers, putting the main focus on development reported within the past three years but without omitting the fundamentals. Graphical abstract image
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Applications of stimuli-responsive nanoscale drug delivery systems in translational research ()
Publication date: Available online 16 November 2017 Source:Drug Discovery Today Author(s): Mengjie Gu, Xin Wang, Tan Boon Toh, Edward Kai-Hua Chow Nanoscale drug delivery systems or nanocarriers have shown tremendous promise in the target-specific delivery of therapeutics as well as diagnostic agents. Additional properties can be introduced into nanocarriers to enhance the bioavailability and targeting efficiency of the transported drugs at diseased sites. Such nanocarriers are usually incorporated with stimuli-responsive components that can be triggered by specific stimuli (e.g., temperature, pH, or enzymes) and further induced by certain biological responses, such as enzyme hydrolysis and molecular conformational changes, leading to the controlled release of the transported molecules at targeted sites. In this review, we discuss various stimuli-responsive nanoscale delivery systems and summarize the current perspectives as well as challenges facing the successful translation of these innovative stimuli-responsive nanocarriers from the bench to the bedside.
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Personalized nanomedicine for CNS diseases ()
Publication date: Available online 15 November 2017 Source:Drug Discovery Today Author(s): Ajeet Kaushik, Rahul Dev Jayant, Vinay Bhardwaj, Madhavan Nair Central nervous system (CNS) diseases are rapidly increasing globally. Currently used therapeutic agents to treat CNS diseases exhibit significant efficacy. However, the inability of these drugs to cross the blood–brain barrier (BBB) and invasiveness of the technologies to achieve localized drug delivery in disease-specific parts of the brain have thwarted pain-free and complete treatment of CNS diseases. Therefore, the safe, non-invasive, and targeted delivery of drugs to the brain using nanoparticles (NPs) is currently receiving considerable research attention. Here, we highlight advances in state-of-the-art personalized nanomedicine for the treatment of CNS diseases (with a focus on dementia), the related challenges, possible solutions, and prospects for nano-enabled personalized medicine.
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The role of fMRI in drug development ()
Publication date: Available online 15 November 2017 Source:Drug Discovery Today Author(s): Owen Carmichael, Adam J. Schwarz, Christopher H. Chatham, David Scott, Jessica A. Turner, Jaymin Upadhyay, Alexandre Coimbra, James A. Goodman, Richard Baumgartner, Brett A. English, John W. Apolzan, Preetham Shankapal, Keely R. Hawkins Functional magnetic resonance imaging (fMRI) has been known for over a decade to have the potential to greatly enhance the process of developing novel therapeutic drugs for prevalent health conditions. However, the use of fMRI in drug development continues to be relatively limited because of a variety of technical, biological, and strategic barriers that continue to limit progress. Here, we briefly review the roles that fMRI can have in the drug development process and the requirements it must meet to be useful in this setting. We then provide an update on our current understanding of the strengths and limitations of fMRI as a tool for drug developers and recommend activities to enhance its utility. Brain fMRI has the potential to become a powerful tool for clinical trials but is currently underutilized. Here, we explain why and present a path forward.
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Drug discovery tomorrow: how to Catapult ourselves into the future ()
Publication date: Available online 14 November 2017 Source:Drug Discovery Today Author(s): Chris Molloy
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Fixed-dose combinations: a potential means to boost drug development for selected drugs ()
Publication date: Available online 14 November 2017 Source:Drug Discovery Today Author(s): Charles Oo, Sherwin K.B. Sy
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Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions ()
Publication date: Available online 13 November 2017 Source:Drug Discovery Today Author(s): Seyed Moein Moghimi Injection/infusion reactions to nanopharmaceuticals (and particulate drug carriers) are idiosyncratic and well documented. The molecular basis of nanoparticle-mediated injection reactions is debatable, with two hypotheses as front-runners. The first is complement-activation-related ‘pseudoallergy’, where a causal role for nanoparticle-mediated complement activation in injection/infusion reactions is considered. However, the second hypothesis (the rapid phagocytic response hypothesis) states a transitional link from robust clearance of nanoparticles (NPs) from the blood by strategically placed responsive macrophages to adverse hemodynamic and cardiopulmonary reactions, regardless of complement activation. Here, I critically examine and discuss these hypotheses. Current experimentally derived evidence appears to be more in support of the rapid phagocytic response hypothesis than of the ‘pseudoallergy’ hypothesis.
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Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs ()
Publication date: Available online 10 November 2017 Source:Drug Discovery Today Author(s): Ashay Jain, Atul Jain, Prahlad Parajuli, Vijay Mishra, Gargi Ghoshal, Bhupinder Singh, Uma Shankar Shivhare, Om Prakash Katare, Prashant Kesharwani Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand–receptor-mediated delivery of drug carriers. Galactose-functionalized nanocarriers open new avenues for the design of highly effective multifunctional, targeted drug delivery systems.
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Galectin-3: mediator of microglia responses in injured brain ()
Publication date: Available online 10 November 2017 Source:Drug Discovery Today Author(s): Reza Rahimian, Louis-Charles Béland, Jasna Kriz Galectin-3 is a pleiotropic protein involved in cell activation, proliferation and migration and plays a pivotal part as an inflammatory mediator in neurodegeneration. Galectin-3 is associated with microglial activation and proliferation after ischemia. Given its putative role as a dynamic fine-tuner of microglia, activation of Galectin-3 provides molecular cues in design of new immunomodulatory strategies for stroke management. This review summarizes recent evidence on the role of Galectin-3 as a mediator of immune responses in damaged brain and mechanisms employed by Galectin-3 to affect microglial function.
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Rare genetic diseases: update on diagnosis, treatment and online resources ()
Publication date: Available online 10 November 2017 Source:Drug Discovery Today Author(s): Robert E. Pogue, Denise P. Cavalcanti, Shreya Shanker, Rosangela V. Andrade, Lana R. Aguiar, Juliana L. de Carvalho, Fabrício F. Costa Rare genetic diseases collectively impact a significant portion of the world’s population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how the collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases.
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Mesoporous silica nanoparticles: a smart nanosystem for management of breast cancer ()
Publication date: Available online 8 November 2017 Source:Drug Discovery Today Author(s): Neelam Poonia, Viney Lather, Deepti Pandita Breast cancer is the second-leading cause of death in women worldwide owing to aggressive metastasis, lack of early diagnosis and poor access to treatment amenities. During the past decade, mesoporous silica nanoparticles (MSNs) have gained ground for the delivery of a wide variety of chemotherapeutic and bioimaging agents owing to their unique characteristics and straightforward fabrication methods. Present research studies based on MSNs have provided various potential insights in their applicability in breast cancer treatment by improving solubility and stability and decreasing the adverse effects of current treatment regimens. This review focuses on the applicability of this novel modality in the management of breast cancer. Inorganic nanoparticles paving the way for better management of breast cancer.
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Contents page 1 ()
Publication date: November 2017 Source:Drug Discovery Today, Volume 22, Issue 11
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Contents page 2 ()
Publication date: November 2017 Source:Drug Discovery Today, Volume 22, Issue 11
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2016 in review: FDA approvals of new molecular entities ()
Publication date: November 2017 Source:Drug Discovery Today, Volume 22, Issue 11 Author(s): Rebekah H. Griesenauer, Michael S. Kinch An overview of drugs approved by FDA in 2016 reveals dramatic disruptions in long-term trends. The number of new molecular entities (NMEs) dropped, reflecting the lowest rate of small-molecule approvals observed in almost five decades. In addition, the pace of industry consolidation slowed substantially. The impact of mergers and acquisitions decreased the total number of organizations with past approval experience and continued research and development (R&D) activities to 102, divided evenly between more established pharmaceutical and newer biotechnology companies. Despite these substantial differences, the industry continued to pursue regulatory incentives, as evidenced by a continued increase in the fraction of NMEs approved using an orphan or priority designation, and almost all oncology drugs approved in 2016 utilized these mechanisms.
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Emerging technologies for prediction of drug candidate efficacy in the preclinical pipeline ()
Publication date: November 2017 Source:Drug Discovery Today, Volume 22, Issue 11 Author(s): Denis Menshykau The pharmaceutical industry is tackling increasingly complex multifactorial diseases, resulting in increases in research & development (R&D) costs and reductions in the success rates for drug candidates during Phase 2 and 3 clinical trials, with a lack of efficacy being the primary reason for drug candidate failure. This implies that the predictive power of current preclinical assays for drug candidate efficacy is suboptimal and, therefore, that alternatives should be developed. Here, I review emerging in vitro, imaging, and in silico technologies and discuss their potential contribution to drug efficacy assessment. Importantly, these technologies are complimentary and can be bundled into the preclinical platform. In particular, patient-on-a-chip recapitulates both human genetics and physiology. The response of a patient-on-a-chip to drug candidate treatment is monitored with light-sheet fluorescent microscopy and fed into the image-analysis pipeline to reconstruct an image-based systems-level model for disease pathophysiology and drug candidate mode of action. Thus, such models could be useful tools for assessing drug candidate efficacy and safety in humans.
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Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery ()
Publication date: November 2017 Source:Drug Discovery Today, Volume 22, Issue 11 Author(s): Nilesh M. Meghani, Hardik H. Amin, Beom-Jin Lee The concept of click chemistry (CC), first introduced by K.B. Sharpless, has been widely adopted for use in drug discovery, novel drug delivery systems (DDS), polymer chemistry, and material sciences. In this review, we outline novel aspects of CC related to drug discovery and drug delivery, with a brief overview of molecular mechanisms underlying each click reaction commonly used by researchers, and the main patents that paved the way for further diverse medicinal applications. We also describe recent progress in drug discovery and polymeric and carbon material-based drug delivery for potential pharmaceutical applications and advancements based on the CC approach, and discuss some intrinsic limitations of this popular conjugation reaction. The use of CC is likely to significantly advance drug discovery and bioconjugation development. Graphical abstract image Click chemistry is set to develop new potential molecules and biomaterials for treatment of various diseases, drug delivery and diagnostics, respectively.
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