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  • Guiding principles of value creation through collaborative innovation in pharmaceutical research
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-20
    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 stage 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.

  • Market entry, power, pharmacokinetics: what makes a successful drug innovation?
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-20
    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 combined. 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.

  • Strategies for the enhanced intracellular delivery of nanomaterials
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-15
    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.

  • Uncovering novel repositioning opportunities using the Open Targets platform
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14
    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.

  • Molecular targets and pathways for the treatment of visceral leishmaniasis
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14
    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.

  • CHEMGENIE: integration of chemogenomics data for applications in chemical biology
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14
    Peter S. Kutchukian, Charlie Chang, Sean J. Fox, Erica Cook, Richard Barnard, David Tellers, Huijun Wang, Dante Pertusi, Meir Glick, Robert P. Sheridan, Iain Wallace, Anne Mai Wassermann

    Increasing amounts of biological data are accumulating in the pharmaceutical industry and academic institutions. However, data do not equal actionable information, and guidelines for appropriate data capture, harmonization, integration, mining, and visualization need to be established to fully harness their 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.

  • Circulatory-cell-mediated nanotherapeutic approaches in disease targeting
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14
    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.

  • High-throughput flow cytometry for drug discovery: principles, applications, and case studies
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-12
    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.

  • Near infrared spectroscopy: a tool for solid-state characterization
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-08
    Rahul B. Chavan, Nallamothu Bhargavi, Anurag Lodagekar, Nalini R. Shastri
  • Revisiting asthma therapeutics: focus on WNT signal transduction
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-07
    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.

  • Towards carborane-functionalised structures for the treatment of brain cancer
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-05
    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.

  • From machine learning to deep learning: progress in machine intelligence for rational drug discovery
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-04
    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.

  • Finding hidden treasures in old drugs: the challenges and importance of licensing generics
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-01
    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.

  • Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-01
    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.

  • RanBPM: a potential therapeutic target for modulating diverse physiological disorders
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-26
    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.

  • Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca–Charles-River-Laboratories strategic relationship
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-26
    Frederic D.C. Martin, Amanda Benjamin, Ruth MacLean, David M. Hollinshead, Claire Landqvist

    In 2012, AstraZeneca entered into a strategic relationship with Charles Rivers 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.

  • Zinc oxide nanoparticles: a promising nanomaterial for biomedical applications
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-25
    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.Teaser: Zinc oxide nanoparticles: how useful will they be in the biomedical sciences?

  • The Warburg effect and glucose-derived cancer theranostics
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-24
    Rakesh K. Tekade, Xiankai Sun
  • Structural Coverage of the Proteome for Pharmaceutical Applications
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-23
    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.

  • Developing PreDICT − a fully integrated data platform for preclinical in vivo data: learning from experience
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-09
    Rhys D.O. Jones, Marie Cooke, James Hinchliffe, Justin Morley, Simon T. Barry

    In vivo models have been crucial for developing our understanding of key processes associated with human disease and developing novel therapeutics. These in vivo studies are becoming increasingly complex, requiring long-term efficacy data and additional supportive datasets such as pharmacokinetic profiles and analysis of multiple biomarkers of pharmacodynamic response and efficacy. Moreover, a new agent will be investigated in many different models and often in combination with other drugs. Despite advances across the industry integrating and analysing complex datasets, management of in vivo data remains an ongoing challenge across the industry. Here, we describe a project that has successfully delivered a working solution to integrate pharmacokinetic, biomarker and efficacy data, independent of therapy area.

  • Tocotrienols: the unsaturated sidekick shifting new paradigms in vitamin E therapeutics
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-05
    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.

  • Stem cells in cardiovascular diseases: turning bad days into good ones
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-04
    Maira Souza de Oliveira, Felipe Saldanha-Araujo, Alfredo Miranda de Goes, Fabricio F. Costa, Juliana Lott de Carvalho

    During the past decade, several types of stem cells have been investigated as promising therapeutic agents for cardiovascular diseases (CVDs). Among them, mesenchymal stem cells (MSCs) were the most investigated stem cell population. Hundreds of clinical trials later, results remain disappointing and far from the revolutionary improvements expected for heart function. In the present review, we address strategies under investigation to boost MSC therapy for CVDs. Pluripotent stem cells (PSCs) are also intended to reach clinical applications for CVDs, but here we suggest that, in the short term, the major impact of PSCs in the cardiovascular field might be at the bench and not the bedside.

  • Drug target residence time: a misleading concept
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-03
    Rutger H.A. Folmer

    Since the importance of drug target residence time was first highlighted more 10 years ago, slow binding kinetics has received much attention in the drug discovery literature, and indeed within pharmaceutical research. However, the residence concept as presented in most papers is supported by rather misleading simulations and arguments, and by examples where compounds are taken out of their pharmacokinetic context. Moreover, fast association is typically more desirable than slow, and advantages of long residence time, notably a potential disconnect between pharmacodynamics (PD) and pharmacokinetics (PK), would be partially or completely offset by slow on-rate. Therefore, plain potency is likely a better predictor of drug development success than is residence time.

  • Polypharmacology of conformationally locked methanocarba nucleosides
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-03
    Kenneth A. Jacobson, Dilip K. Tosh, Kiran S. Toti, Antonella Ciancetta
  • Age-related macular degeneration: current therapeutics for management and promising new drug candidates
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-03
    Afrah J. Abd, Rupinder K. Kanwar, Jagat R. Kanwar

    Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment among the aged population. Because the elderly population constitutes a large percentage among society, visual loss due to AMD has become a growing problem. Despite the advances made in developing therapeutics, there is still no satisfactory treatment. The limitations of the available treatments are related to the absence of a potent, noninvasive therapy. Furthermore, some of the available drugs target angiogenesis and create a hypoxic environment that augments further angiogenesis. Therefore, it is reasonable to consider eye integrity and the correlation between hypoxia and angiogenesis before developing successful drugs. This review highlights issues regarding the available therapeutic strategies and explores whether AMD can be managed by employing specific nanoformulations.

  • Myotonic dystrophy: candidate small molecule therapeutics
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-02
    Piotr Konieczny, Estela Selma-Soriano, Anna S. Rapisarda, Juan M. Fernandez-Costa, Manuel Perez-Alonso, Ruben Artero

    Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing and therapeutic gene modulation.

  • Label-free technology and patient cells: from early drug development to precision medicine
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-01
    Julia M. Hillger, Wai-Ling Lieuw, Laura H. Heitman, Adriaan P. IJzerman
  • Quantifying the allosteric interactions within a G-protein-coupled receptor heterodimer
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-27
    Bin Zhou, Jesús Giraldo

    G-protein-coupled receptors are central to signal transduction and cell communication. The possibility that cells use receptor heteromerization to modulate individual receptor pathways is a surmise that cannot be precluded. Given the complexity of these processes, mathematical models contribute to understanding how receptors and their respective ligands regulate signaling. Here, a mathematical model is presented that quantifies the allosteric interactions within a receptor heterodimer. The model is based on the operational model of allosterism including constitutive receptor activity, which provides the pharmacological analysis of heteromerization with well-established and widely used modeling and fitting procedures.

  • Molecular epigenetic targets for liver diseases: current challenges and future prospects
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-25
    Robert Zeidler, Bruno Leonardo de Freitas Soares, Augustinus Bader, Shibashish Giri
  • Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-25
    Nilesh M. Meghani, Hardik H. Amin, Beom-Jin Lee
  • Mu-Opioid receptor-biased ligands: safe, pain-free analgesics
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-22
    Abraham Madariaga-Mazón, Andrés F. Marmolejo-Valencia, Yangmei Li, Lawrence Toll, Richard A. Houghten, Karina Martinez-Mayorga

    Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased μ-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand–receptor recognition process.

  • Improving the economics of NASH/NAFLD treatment through the use of systems biology
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-20
    Jim Bosley, Christofer Boren, Sunjae Lee, Morten Grøtli, Jens Nielsen, Mathias Uhlen, Jan Boren, Adil Mardinoglu

    Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH. We discuss the potential broader use of genome-scale metabolic models and integrated networks in the validation of drug targets, which could facilitate more productive and efficient drug development decisions for the treatment of NASH.

  • Engineered nanoparticles for the detection, treatment and prevention of atherosclerosis: how close are we?
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-18
    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.

  • Aggregation-induced emission probes for cancer theranostics
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-13
    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.

  • Curcumin and its topical formulations for wound healing applications
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-12
    Chandana Mohanty, Sanjeeb K. Sahoo
  • Drugs as habitable planets in the space of dark chemical matter
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-11
    Vishal B. Siramshetty, Robert Preissner
  • Dendrimer nanohybrid carrier systems: an expanding horizon for targeted drug and gene delivery
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-08
    Prashant Kesharwani, Avinash Gothwal, Arun K. Iyer, Keerti Jain, Manish K. Chourasia, Umesh Gupta

    Highly controllable dendritic structural design means dendrimers are a leading carrier in drug delivery applications. Dendrimer- and other nanocarrier-based hybrid systems are an emerging platform in the field of drug delivery. This review is a compilation of increasing reports of dendrimer interactions, such as dendrimer–liposome, dendrimer–carbon-nanotube, among others, known as hybrid carriers. This should prompt entirely new research with promising results for these hybrid carriers. It is assumed that such emerging hybrid nanosystems – from combining two already-established drug delivery platforms – could lead the way for the development of newer delivery systems with multiple applicability for latent theranostic applications in the future.

  • Efficacy of non-vitamin-K antagonist oral anticoagulants for intracardiac thrombi resolution in nonvalvular atrial fibrillation
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-08
    Esteban Orenes-Piñero, María A. Esteve-Pastor, Mariano Valdés, Gregory Y.H. Lip, Francisco Marín

    Intracardiac thrombus is a potentially life-threatening condition associated with atrial fibrillation (AF), with a high risk of embolic complications. Oral anticoagulation (OAC) therapy is the first-line treatment for its prevention or resolution. For many patients, traditional OAC treatment using vitamin K antagonists (VKAs; e.g., warfarin) is limited by several factors and the advent of non-VKA oral anticoagulants (NOACs), with improved efficacy and safety profiles, has provided additional treatment options. However, studies are limited in number and are mostly case reports or series, with only one published modest-size prospective multicenter cohort study for rivaroxaban. No randomized controlled trials have been performed. Given the available data thus far, albeit weak, NOACs offer a possible alternative to VKAs for treating intracardiac thrombi.

  • Implementing QM in docking calculations: is it a waste of computational time?
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-05
    Adebayo A. Adeniyi, Mahmoud E.S. Soliman
  • Microfluidic technologies for anticancer drug studies
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-04
    Karolina P. Valente, Sultan Khetani, Ahmad R. Kolahchi, Amir Sanati-Nezhad, Afzal Suleman, Mohsen Akbari

    The study of cancer growth mechanisms and the determination of the efficacy of experimental therapeutics are usually performed in two-dimensional (2D) cell culture models. However, these models are incapable of mimicking complex interactions between cancer cells and the environment. With the advent of microfluidic technologies, the combination of multiple cell cultures with mechanical and biochemical stimuli has enabled a better recapitulation of the three-dimensional (3D) tumor environment using minute amounts of reagents. These models can also be used to study drug transport, hypoxia, and interstitial pressure within the tumor. In this review, we highlight the applications of microfluidic-based models in anticancer drug studies and provide a perspective on the future of the clinical applications of microfluidic systems for anticancer drug development.

  • 2016 in review: FDA approvals of new molecular entities
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-04
    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.

  • Mouse models of nonalcoholic steatohepatitis in preclinical drug development
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-04
    Henrik H. Hansen, Michael Feigh, Sanne S. Veidal, Kristoffer T. Rigbolt, Niels Vrang, Keld Fosgerau

    Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH. Available mouse models of NASH address different aspects of the disease, have varying clinical translatability, and, therefore, also show different utility in drug discovery.

  • A comprehensive review on polyelectrolyte complexes
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-03
    Venkata S. Meka, Manprit K.G. Sing, Mallikarjuna R. Pichika, Srinivasa R. Nali, Venkata R.M. Kolapalli, Prashant Kesharwani

    Global research on polyelectrolytes at a fundamental and applied level is intensifying because the advantages of sustainability are being accepted in academia and industrial research settings. During recent decades, polyelectrolytes became one of the most attractive subjects of scientific research owing to their great potential in the areas of advanced technologies. Polyelectrolytes are a type of polymer that have multitudinous ionizable functional groups. Ionized polyelectrolytes in solution can form a complex with oppositely charged polyelectrolytes — a polyelectrolyte complex (PEC). The present article provides a comprehensive review on PECs and their classification, theory and characterization, as well as a critical analysis of the current research.

  • The 1,2,3-triazole ring as a bioisostere in medicinal chemistry
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-01
    Elisa Bonandi, Michael S. Christodoulou, Gaia Fumagalli, Dario Perdicchia, Giulio Rastelli, Daniele Passarella

    1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compounds characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active molecules. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples.

  • Switching off CD73: a way to boost the activity of conventional and targeted antineoplastic therapies
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-07-01
    Luca Antonioli, Sergey V. Novitskiy, Kris F. Sachsenmeier, Matteo Fornai, Corrado Blandizzi, György Haskó

    Over the past few years, several preclinical studies have highlighted the value of CD73 (ecto-5′-nucleotidase) as a potential therapeutic target for cancer therapy. Indeed, the pharmacological blockade of CD73, via monoclonal antibodies or small molecules, has promise in counteracting cancer development, growth and spread. Synergistic combinations of anti-CD73 drugs with conventional cancer treatments (i.e., chemotherapy, radiation therapy, immunotherapy, targeted therapy) have increased therapeutic potential. In this review, we discuss the potential synergistic effects of CD73 blockers and conventional antineoplastic therapies in the treatment of cancer.

  • Industrial medicinal chemistry insights: neuroscience hit generation at Janssen
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-29
    Gary Tresadern, Frederik J.R. Rombouts, Daniel Oehlrich, Gregor Macdonald, Andres A. Trabanco

    The role of medicinal chemistry has changed over the past 10 years. Chemistry had become one step in a process; funneling the output of high-throughput screening (HTS) on to the next stage. The goal to identify the ideal clinical compound remains, but the means to achieve this have changed. Modern medicinal chemistry is responsible for integrating innovation throughout early drug discovery, including new screening paradigms, computational approaches, novel synthetic chemistry, gene-family screening, investigating routes of delivery, and so on. In this Foundation Review, we show how a successful medicinal chemistry team has a broad impact and requires multidisciplinary expertise in these areas.

  • Progranulin as a biomarker and potential therapeutic agent
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-23
    Vanessa Abella, Jesús Pino, Morena Scotece, Javier Conde, Francisca Lago, Miguel Angel Gonzalez-Gay, Antonio Mera, Rodolfo Gómez, Ali Mobasheri, Oreste Gualillo

    Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases.

  • Establishing rarity in the context of orphan medicinal product designation in the European Union
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-21
    Stelios Tsigkos, Matthias Philipp Hofer, Maria Elzbieta Sheean, Segundo Mariz, Kristina Larsson, Frauke Naumann-Winter, Laura Fregonese, Bruno Sepodes

    In the European Union (EU) legislative framework for orphan medicinal product designation, establishing that a condition affects not more than five in 10,000 people is a prerequisite for applications based on rarity. Demonstrating this requirement to the Committee of Orphan Medicinal Products (COMP) can be a particularly challenging task for sponsors. Here, we identify and examine three common issues with the estimation of prevalence in orphan drug applications in the EU (the discernment between diagnosed and undiagnosed cases; the duration of the disease; and the need for an explicit contemporary conclusion) as critical factors for acceptable prevalence estimation. These concerns are discussed in detail based on recent examples of applications, which are reflected in published European Medicines Agency (EMA) documents.

  • Do large mergers increase or decrease the productivity of pharmaceutical R&D?
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-21
    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.

  • Leishmaniasis drug discovery: recent progress and challenges in assay development
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-21
    Bilal Zulfiqar, Todd B. Shelper, Vicky M. Avery

    Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates. It is therefore imperative that more physiologically relevant assays are developed to identify anti-leishmanial compounds. This review provides an overview of the disease, current treatment options and compares the various technologies and assay formats currently available for leishmanial drug discovery.

  • Current progress in antivascular tumor therapy
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-16
    Yi-Ju Ho, Tzu-Chia Wang, Ching-Hsiang Fan, Chih-Kuang Yeh
  • From flamingo dance to (desirable) drug discovery: a nature-inspired approach
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-15
    Aminael Sánchez-Rodríguez, Yunierkis Pérez-Castillo, Stephan C. Schürer, Orazio Nicolotti, Giuseppe Felice Mangiatordi, Fernanda Borges, M. Natalia D.S. Cordeiro, Eduardo Tejera, José L. Medina-Franco, Maykel Cruz-Monteagudo
  • Advances in antibody–drug conjugates: A new era of targeted cancer therapy
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-13
    Samaresh Sau, Hashem O. Alsaab, Sushil Kumar Kashaw, Katyayani Tatiparti, Arun K. Iyer

    Antibody–drug conjugates (ADCs), a potent class of anticancer therapeutics, comprise a high-affinity antibody (Ab) and cytotoxic payload coupled via a suitable linker for selective tumor cell killing. In the initial phase of their development, two ADCs, Mylotarg®, and Adcetris® were approved by the US Food and Drug Administration (FDA) for treating hematological cancer, but the real breakthrough came with the discovery of the breast cancer-targeting ADC, Kadcyla®. With advances in bioengineering, linker chemistry, and potent cytotoxic payload, ADC technology has become a more powerful tool for targeted cancer therapy. In addition, ADCs with improved safety using humanized Abs with a unified ‘drug:antibody ratio’ (DAR) have been achieved. Concomitantly, there has been a significant increase in the number of clinical trials with anticancer ADCs with high translation potential.

  • Lipid–polymer hybrid nanoparticle-mediated therapeutics delivery: advances and challenges
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-06
    Rajendran J.C. Bose, Rramaswamy Ravikumar, Vengadeshprabu Karuppagounder, Devasier Bennet, Sabarinathan Rangasamy, Rajarajan A. Thandavarayan

    With rapid advances in nanomedicine, lipid–polymer hybrid nanoparticles (LPHNPs) have emerged as promising nanocarriers for several biomedical applications, including therapeutics delivery and biomedical imaging. Significant research has been dedicated to biomimetic or targeting functionalization, as well as controlled and image-guided drug-release capabilities. Despite this research, the clinical translation of LPHNP-mediated therapeutics delivery has progressed incrementally. In this review, we discuss the recent advances in and challenges to the development and application of LPHNPs, present examples to demonstrate the advantages of LPHNPs in therapeutics delivery and imaging applications, and discuss the translational obstacles to LPHNP technology.

  • Understanding the checkpoint blockade in lung cancer immunotherapy
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-06-06
    Maria Giovanna Dal Bello, Angela Alama, Simona Coco, Irene Vanni, Francesco Grossi

    Immunotherapies have changed the treatment strategy of some types of tumor including melanoma and, more recently, non-small-cell lung cancer (NSCLC). Immune checkpoints are crucial for the maintenance of self-tolerance and it is known that some tumors use checkpoint systems to evade antitumor immune response. The treatment of advanced NSCLC by immune-checkpoint blockade targeting the programmed cell death protein-1 (PD1/PDL1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) pathways has led to significant clinical benefit either as monotherapy or in combination therapy. Moreover, checkpoint receptors such as lymphocyte activation gene 3 protein (LAG3), T-cell immunoglobulin mucin domain 3 (TIM3) and killer immunoglobulin-like receptors (KIRs) are also being investigated as potential immunotherapeutic targets. This review focuses on the mechanisms of action of the main checkpoint inhibitors in lung cancer and presents the most relevant results from preclinical and clinical studies on immune-based treatments.

  • Targeting survivin for therapeutic discovery: past, present, and future promises
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-05-31
    Robert C. Peery, Jing-Yuan Liu, Jian-Ting Zhang

    Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery.

  • Gastric bypass surgery mimetic approaches
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-05-30
    Brian R. Boettcher

    Gastric bypass surgery is effectively a polypharmacological approach for treatment of obesity, type 2 diabetes and nonalcoholic steatohepatitis (NASH). The gastric bypass mimetic approaches reviewed are fixed-dose combinatorial pharmacological approaches. There are two key concepts incorporated into these gastric bypass surgery mimetic approaches. The first key concept is that the combination of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) is essential for success of any gastric bypass surgery mimetic approach. This combination affords the potential for durable weight loss, glycemic control and reduction in liver lipids. The second key concept is that a fixed-dose combination approach is preferred over post-approval combination of the individual components because the individual components alone often lack sufficient efficacy for development.

  • Electrospun polymeric micro/nanofibrous scaffolds for long-term drug release and their biomedical applications
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-05-24
    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.

  • Strategies for targeted drug delivery in treatment of colon cancer: current trends and future perspectives
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-05-22
    Antara Banerjee, Surajit Pathak, Vimala Devi Subramanium, Dharanivasan G., Ramachandran Murugesan, Rama S. Verma
  • Emerging technologies for prediction of drug candidate efficacy in the preclinical pipeline
    Drug. Discov. Today (IF 6.369) Pub Date : 2017-05-22
    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.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.