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Drug Discovery Today
Journal Prestige (SJR): 2.008
Citation Impact (citeScore): 6
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ISSN (Print) 1359-6446 - ISSN (Online) 1878-5832
Published by Elsevier Homepage  [3161 journals]
  • Reporter gene imaging and its role in imaging-based drug development
    • Abstract: Publication date: Available online 16 January 2020Source: Drug Discovery TodayAuthor(s): Faiq A. Shaikh, E. Kurtys, O. Kubassova, D. RoettgerReporter gene imaging (RGI) is described as the methodology that involves imaging of the encoding proteins that can be used as surrogate markers when fused with regulatory regions of the gene of interest. It provides a means to indirectly monitor molecular processes that are implicated in the pathophysiology of several diseases. The modalities utilized in RGI include MRI, PET, SPECT, as well as optical imaging modalities, such as bioluminescence and fluorescence. RGI provides a highly specific way to qualitatively and quantitatively assess cell targeting, transfection, protein expression and other intracellular processes, which are valuable for pharmacodynamic and pharmacokinetic assessment of cellular, gene and oncolytic viral therapeutics.
       
  • Learning and augmenting natural processes: potential means of combating
           antimicrobial resistance from a drug R&D perspective
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Charles Oo, Sherwin K.B. Sy
       
  • Emergence of allosteric drug-resistance mutations: new challenges for
           allosteric drug discovery
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Shaoyong Lu, Yuran Qiu, Duan Ni, Xinheng He, Jun Pu, Jian ZhangAllosteric drugs have several significant advantages over traditional orthosteric drugs, encompassing higher selectivity and lower toxicity. Although allosteric drugs have potential advantages as therapeutic agents to treat human diseases, allosteric drug-resistance mutations still occur, rendering these drugs ineffective. Here, we review the emergence of allosteric drug-resistance mutations with an emphasis on examples covering clinically important therapeutic targets, including Breakpoint cluster region-Abelson tyrosine kinase (Bcr-Abl), Akt kinase [also called Protein Kinase B (PKB)], isocitrate dehydrogenase (IDH), MAPK/ERK kinase (MEK), and SRC homology 2 domain-containing phosphatase 2 (SHP2). We also discuss challenges associated with tackling allosteric drug resistance and the possible strategies to overcome this issue.
       
  • Site-specific bioconjugation and self-assembly technologies for
           multi-functional biologics: on the road to the clinic
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Sung In LimThe expanding portfolio of biotherapeutics both in the research and development (R&D) and market sectors is shaping new opportunities towards multifunctional biologics (MFBs). The combination of new or pre-existing therapeutic agents into a single multifunctional format makes it possible to develop new pharmacological actions to significantly improve their efficacy and safety. In this review, I focus on novel platform technologies that are being exploited in the biotech industry to produce MFBs with potential therapeutic benefits that include half-life extension, targeted delivery, T cell engagement, and improved vaccination. In this regard, technologies of key importance are site-specific bioconjugation and self-assembly, which allow homogeneous, defined, and scalable process developments for several MFBs that are advancing towards clinical applications.
       
  • Heterogeneous surface-modified nanoplatforms for the targeted therapy of
           haematological malignancies
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Sanjay Kulkarni, Abhijeet Pandey, Srinivas MutalikHere, we focus on nanoparticle (NP)-based platforms for the targeted therapy of haematological malignancies (HMs), providing an overview of surface-modified nanoplatforms, such as aptamer-, metal-, nucleic acid-, toxin, and peptide-modified NPs, for the efficient targeting of tumor cells. We discuss NPs targeting subcellular compartments, including mitochondria, nucleus and Golgi apparatus, for enhanced therapy of HMs. We also review stimuli-responsive nanoplatforms for modulating site-specific release of drugs. We provide insight into alternative modes of therapy, such as phototherapy, gene therapy, dendritic cell (DC) therapy, and radiotherapy, highlighting recent advances in the treatment of HMs.Graphical abstractGraphical abstract for this article
       
  • Physicochemical properties affecting the fate of nanoparticles in
           pulmonary drug delivery
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Qiaoyu Liu, Jian Guan, Lu Qin, Xin Zhang, Shirui MaoThe inhaled delivery of nanomedicines has attracted much attention in the treatment of lung diseases or systemic diseases. However, there is a lack of understanding about their fate upon lung delivery. Thus, the objective of this review is to summarize physicochemical properties affecting the fate of nanoparticles after deposition in the lung. First, physiological structure and characteristics of the lung are described. Thereafter, physicochemical properties that could influence the clearance and translocation of nanoparticles in the lung are discussed, including particle size, surface charge and surface hydrophilicity. It is believed that, with a better understanding of the fate of nanoparticles in the lung, it will broaden their application in inhalation for a better therapeutic effect in the future.Graphical abstractGraphical abstract for this article
       
  • Iron oxide nanoparticles for therapeutic applications
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Edouard AlphandéryIn nanomedicine, iron oxide nanoparticles are at an advanced stage, being commercialized for cancer treatment and iron-deficiency anemia treatment. Their therapeutic efficacy comes from their ability to target a tissue, activate a drug, locally produce a temperature increase following (or not) the application of an external source of energy, modify genes or activate various biological materials, or replace diseased cells by stem cells. Owing to these various mechanisms of action, they can potentially be used for treating a whole range of different diseases, making them more appealing than conventional drugs that target a more limited number of indications.
       
  • Activity-based proteomic profiling: application of releasable linker in
           photoaffinity probes
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Jin Wang, Qinhua Chen, Yuanyuan Shan, Xiaoyan Pan, Jie ZhangCombining releasable chemical crosslinkers with photoaffinity probes represents a valuable tool for identifying protein–protein interactions (PPIs). The biomacromolecule photoaffinity probe prepared by using releasable photoaffinity linkers can be used to exploring PPIs by triggering release of the releasable group. More importantly, it can overcome the shortcomings of macromolecular photoaffinity probes without label transfer functionality to accurately confirm defects in specific structural sites. It shows particular promise for research exploring the interaction of unknown proteins and transient–weak PPIs in living organisms to discover new drug targets. In this review, we highlight recent progress in the development and application of chemical releasable linkers in photoaffinity probes. Several comparative studies are described in which the efficiency of various photoaffinity probes are compared.
       
  • Clinical applications of nanomedicine in cancer therapy
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Mohammad Norouzi, Mehrnaz Amerian, Mahshid Amerian, Fatemeh AtyabiGraphical abstractGraphical abstract for this article
       
  • Neurovascular glucocorticoid receptors and glucocorticoids: implications
           in health, neurological disorders and drug therapy
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Sherice Williams, Chaitali GhoshGlucocorticoid receptors (GRs) are ubiquitous transcription factors widely studied for their role in controlling events related to inflammation, stress and homeostasis. Recently, GRs have reemerged as crucial targets of investigation in neurological disorders, with a focus on pharmacological strategies to direct complex mechanistic GR regulation and improve therapy. In the brain, GRs control functions necessary for neurovascular integrity, including responses to stress, neurological changes mediated by the hypothalamic-pituitary-adrenal axis and brain-specific responses to corticosteroids. Therefore, this review will examine GR regulation at the neurovascular interface in normal and pathological conditions, pharmacological GR modulation and glucocorticoid insensitivity in neurological disorders.
       
  • Design strategies for programmable oligonucleotide nanotherapeutics
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Fitsum Feleke Sahle, Tao L. LoweGraphical abstractGraphical abstract for this article
       
  • A new approach to the diagnosis and treatment of atherosclerosis: the era
           of the liposome
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Nasim Kiaie, Armita Mahdavi Gorabi, Peter E. Penson, Gerald Watts, Thomas P. Johnston, Maciej Banach, Amirhossein SahebkarThe consequences of atherosclerotic cardiovascular disease (ASCVD) include myocardial infarction, ischemic stroke, and angina pectoris, which are major causes of mortality and morbidity worldwide. Despite current therapeutic strategies to reduce risk, patients still experience the consequences of ASCVD. Consequently, a current goal is to enhance visualization of early atherosclerotic lesions to improve residual ASCVD risk. The uses of liposomes, in the context of ASCVD, can include as contrast agents for imaging techniques, as well as for the delivery of antiatherosclerotic drugs, genes, and cells to established sites of plaque. Additionally, liposomes have a role as vaccine adjuvants against mediators of atherosclerosis. Here. we review the scientific and clinical evidence relating to the use of liposomes in the diagnosis and management of ASCVD.
       
  • Understanding the variability of the S1′ pocket to improve matrix
           metalloproteinase inhibitor selectivity profiles
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Aleix Gimeno, Raúl Beltrán-Debón, Miquel Mulero, Gerard Pujadas, Santiago Garcia-VallvéMatrix metalloproteinases (MMPs) are a family of proteins involved in a range of pathologies. Given that MMP broad-spectrum inhibition is associated with severe adverse effects, selectivity has become a priority in the design of MMP inhibitors, and is often achieved by targeting the variable S1′ pocket. However, the specific characteristics of the S1′ pocket that determine inhibitor selectivity are often not described and, in many cases, challenging to identify. In this review, we investigate the variability of the S1′ pocket across the MMP family, and propose explanations for the selectivity of previously described inhibitors. These analyses provide valuable insights into how to design novel inhibitors selective for a given MMP.
       
  • Chemometrics: a complementary tool to guide the isolation of
           pharmacologically active natural products
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Axhell A. Cornejo-Báez, Luis M. Peña-Rodríguez, Radamés Álvarez-Zapata, Maribel Vázquez-Hernández, Alberto Sánchez-Medina
       
  • Mind the gap! A survey of the challenges of biomarker commercialization
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Susan Raths, Sven Parkel, Jesper Bredmose, Valérie Daussin‘Mind the gap!’ refers to both the gap between the identification and validation of biomarkers and the gap in knowledge between the stakeholder groups, where the researchers who discover the biomarkers often have little knowledge about the commercialization process. This gap is addressed here in a survey with relevant stakeholders conducted by the project ‘Biomarker Commercialization’ (BIC).
       
  • Dual-peptide ligand masks: a proposed treatment approach to stop prion
           disease dementias
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Kevin RoePrion disease dementias are currently not practically treatable. However, a proposed treatment approach using specifically targeted dual-peptide ligand masks can mask prion surface proteins and treat specific prion diseases. Different approaches might be used to treat these prion diseases. One treatment introduces genetically modified cells into the gastrointestinal tract or other locations to produce dual-peptide ligand masks; and another treatment introduces only the dual-peptide ligand masks into the center of prion infections to mask prion surface proteins. An independent group introduced genetically modified therapeutic bacteria into large numbers of mammals, including several human volunteers, with safe and effective experimental results, without long-term colonization by the bacteria, which experimentally supports the feasibility of the first treatment. These approaches offer several advantages compared with other potential treatments against prion diseases in humans.
       
  • The importance of target binding kinetics for measuring target binding
           affinity in drug discovery: a case study from a CRF1 receptor antagonist
           program
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Sam R.J. Hoare, Beth A. Fleck, John P. Williams, Dimitri E. GrigoriadisIn drug discovery, it is essential to accurately measure drug–target binding affinity. Here, we revisit the fact that target binding kinetics impact the measurement of affinity, using a case study: development of corticotropin-releasing factor antagonists. Slow dissociation of the drug–target complex results in affinity assays being far from equilibrium, which results in erroneous estimates of affinity. This scenario can impair prediction of human dosing, assessment of target selectivity, identification of high-affinity ligands and determination of SAR. We describe strategies to detect lack of equilibration in affinity assays and methods to correctly measure affinity of slowly dissociating compounds. These considerations will facilitate drug discovery by ensuring reliable measurement of drug–target binding affinity.Graphical abstractGraphical abstract for this article
       
  • Synthetic biology – reimagine drug discovery
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Stephanie Brooking
       
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    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s):
       
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    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s):
       
  • A drug-likeness toolbox facilitates ADMET study in drug discovery
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Chen-Yang Jia, Jing-Yi Li, Ge-Fei Hao, Guang-Fu YangUndesirable pharmacokinetic (PK) properties or unacceptable toxicity are the main causes of the failure of drug candidates at the clinical trial stage. Since the concept of drug-likeness was first proposed, it has become an important consideration in the selection of compounds with desirable bioavailability during the early phases of drug discovery. Over the past decade, online resources have effectively facilitated drug-likeness studies in an economical and time-efficient manner. Here, we provide a comprehensive summary and comparison of current accessible online resources, in terms of their key features, application fields, and performance for in silico drug-likeness studies. We hope that the assembled toolbox will provide useful guidance to facilitate future in silico drug-likeness research.Graphical abstractGraphical abstract for this article
       
  • Enhancing the potential preclinical and clinical benefits of quercetin
           through novel drug delivery systems
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Rubiya Khursheed, Sachin Kumar Singh, Sheetu Wadhwa, Monica Gulati, Ankit AwasthiQuercetin is reported to have numerous pharmacological actions, including antidiabetic, anti-inflammatory and anticancer activities. The main mechanism responsible for its pharmacological activities is its ability to quench reactive oxygen species (ROS) and, hence, decrease the oxidative stress responsible for the development of various diseases. Despite its proven therapeutic potential, the clinical use of quercetin remains limited because of its low aqueous solubility, bioavailability, and substantial first-pass metabolism. To overcome this, several novel formulations have been reported. In this review, we focus on the applications of quercetin extract as well as its novel formulations for treating different disorders. We also examine its proposed mechanism of action of quercetin.
       
  • Drug-induced liver injury severity and toxicity (DILIst): binary
           classification of 1279 drugs by human hepatotoxicity
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Shraddha Thakkar, Ting Li, Zhichao Liu, Leihong Wu, Ruth Roberts, Weida TongDrug-induced liver injury (DILI) is of significant concern to drug development and regulatory review because of the limited success with existing preclinical models. For developing alternative methods, a large drug list is needed with known DILI severity and toxicity. We augmented the DILIrank data set [annotated using US Food and Drug Administration (FDA) drug labeling)] with four literature datasets (N>350 drugs) to generate the largest drug list with DILI classification, called DILIst (DILI severity and toxicity). DILIst comprises 1279 drugs, of which 768 were DILI positives (increase of 65% from DILIrank), whereas 511 were DILI negatives (increase of 65%). The investigation of DILI positive–negative distribution across various therapeutic categories revealed the most and least frequent DILI categories. Thus, we consider DILIst to be an invaluable resource for the community to improve DILI research.Graphical abstractGraphical abstract for this article
       
  • Decoy oligodeoxynucleotide technology: an emerging paradigm for breast
           cancer treatment
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Maryam Mahjoubin Tehran, Samaneh Rezaei, Amin Jalili, Seyed Hamid Aghaee-Bakhtiari, Amirhossein SahebkarBreast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, which is resistant to conventional therapies. Therefore, there is an urgent need to identify new therapies for treating incurable breast cancer in patients. Decoy oligodeoxynucleotides (ODNs) are synthetic oligonucleotides that have a high affinity for a specific transcription factor and can be transfected into target cells to bind to their respective target and alter gene transcription. With these powerful tools available, it is highly possible to effectively regulate the expression of genes that are involved in the pathogenesis of breast cancer. Here, we highlight the studies using decoy ODNs for the development of novel therapies against breast cancer.
       
  • Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid
           nanocarrier systems: status quo and outlook
    • Abstract: Publication date: January 2020Source: Drug Discovery Today, Volume 25, Issue 1Author(s): Fakhara Sabir, Ruba Ismail, Ildiko CsokaGlioblastoma multiforme (GBM) is one of the most devastating and deadly types of tumor. Among all the present treatment strategies, the utmost prerequisite is prolonged intervention at the malignant site. The blood–brain barrier (BBB) is the bottleneck in the delivery of anti-GBM drugs and invasive treatment comes with many pitfalls. This review will discuss the potential of embedding antitumor drugs into nanocarriers for intranasal delivery. Additionally, it emphasizes the significance of applying quality by design (QbD) methodology from the early development stages to ensure the high quality, safety and efficacy of the developed carrier system.Graphical abstractGraphical abstract for this article
       
  • Nonclinical data supporting orphan medicinal product designations in the
           area of rare infectious diseases
    • Abstract: Publication date: Available online 5 November 2019Source: Drug Discovery TodayAuthor(s): Maria E. Sheean, Eva Malikova, Dinah Duarte, Giuseppe Capovilla, Laura Fregonese, Matthias P. Hofer, Armando Magrelli, Segundo Mariz, Fernando Mendez-Hermida, Robert Nistico, Tim Leest, Nikolaos V. Sipsas, Stelios Tsigkos, Dinko Vitezic, Kristina Larsson, Bruno Sepodes, Violeta Stoyanova-Beninska
       
  • A special exception for CBD in foods and supplements'
    • Abstract: Publication date: Available online 3 November 2019Source: Drug Discovery TodayAuthor(s): Patricia J. Zettler, Erika Lietzan
       
  • Changing biotechnology dynamics — a blessing or a curse'
    • Abstract: Publication date: Available online 1 November 2019Source: Drug Discovery TodayAuthor(s): Merve Memisoglu
       
  • Key indicators of phase transition for clinical trials through machine
           learning
    • Abstract: Publication date: Available online 8 January 2020Source: Drug Discovery TodayAuthor(s): Felipe Feijoo, Michele Palopoli, Jen Bernstein, Sauleh Siddiqui, Tenley E. AlbrightA significant number of drugs fail during the clinical testing stage. To understand the attrition of drugs through the regulatory process, here we review and advance machine-learning (ML) and natural language-processing algorithms to investigate the importance of factors in clinical trials that are linked with failure in Phases II and III. We find that clinical trial phase transitions can be predicted with an average accuracy of 80%. Identifying these trials provides information to sponsors facing difficult decisions about whether these higher risk trials should be modified or halted. We also find common protocol characteristics across therapeutic areas that are linked to phase success, including the number of endpoints and the complexity of the eligibility criteria.
       
  • An industrial approach towards solid dosage development for first-in-human
           studies: application of predictive science and lean principles
    • Abstract: Publication date: Available online 8 January 2020Source: Drug Discovery TodayAuthor(s): Dhaval R. Kalaria, Keith Parker, Gavin K. Reynolds, Johanna LaruTablet development is challenging during early clinical phases of drug discovery because of dose uncertainty, limited active pharmaceutical ingredient availability, and short lead times. Here, we introduce a new framework to expedite product development using a suite of in-house and commercially available predictive tools developed through the integration of computer modelling and material-sparing characterisation methods. The strategy underpins the use of dry granulation for formulation development with guidance on scale-up and manufacturability to achieve ‘First Time Right’. We present an analytical strategy based on predictive science with a focus on stability, and shelf-life-related attributes to assure product quality. Thus, we provide a holistic approach towards robust, scientific product development through integrated project knowledge and risk-based approaches, delivering significant savings in both material and resources.
       
  • The role of P2Y6R in cardiovascular diseases and recent development of
           P2Y6R antagonists
    • Abstract: Publication date: Available online 8 January 2020Source: Drug Discovery TodayAuthor(s): Mengze Zhou, Weiwei Wang, Yehong Li, Qian Zhang, Hui Ji, Huanqiu Li, Qinghua HuAs a member of the P2Y receptor family with a typical 7-transmembrane structure, P2Y6 purinergic receptor (P2Y6R) belongs to the G-protein-coupled nucleotide receptor activating the phospholipase-C signaling pathway. P2Y6R is widely involved in a range of human diseases, including atherosclerosis and other cardiovascular diseases, gradually attracting attention owing to its inappropriate or excessive activation. In addition, it was reported that P2Y6R might regulate inflammatory responses by governing the maturation and secretion of proinflammatory cytokines. Hence, several P2Y6R antagonists have been subjected to evaluation as new therapeutic strategies in recent years. This review was aimed at summarizing the role of P2Y6R in the pathogenesis of cardiovascular diseases, with an insight into the recent progress on discovery of P2Y6R antagonists.
       
  • Critical considerations in the formulation development of parenteral
           biologic drugs
    • Abstract: Publication date: Available online 8 January 2020Source: Drug Discovery TodayAuthor(s): Bilikallahalli K. Muralidhara, Marcus WongBiopharmaceuticals, unlike chemically synthesized small-molecule drugs, are marginally stable, with most of them requiring 3D structures to retain their activity and/or potency. This implies challenges to formulate these molecules for a shelf life>2 y of and also to minimize the cost of goods for manufacturing. Patient compliance has become a key consideration in the design and development of suitable dosage forms in the modernized world. Thus, here we describe different classes of biological therapeutic, with an emphasis on molecular properties, formulation challenges, and development strategies. We also present statistics on the different classes of approved biologic drugs and dosage forms.
       
  • New paradigm for expediting drug development in Asia
    • Abstract: Publication date: Available online 8 January 2020Source: Drug Discovery TodayAuthor(s): Iris Rajman, Masaru Hirano, Wataru Honma, Sylvia ZhaoSome Asian regulators currently require Phase I data in Asians before joining global Phase II/III trials. Here, we discuss inherent limitations of Phase I ethnic sensitivity studies (ESS) to identify potential interethnic differences. We review recent new drug applications (NDAs) for Japan and China to critically assess the value of separate ESSs in Asian populations. Given that the observed value of ESS was limited, we propose a new global drug development paradigm: if relevant safety, pharmacokinetic (PK), and pharmacogenetic (PG) data are available from the original Phase I study population, it might be possible to extrapolate those data to Asian populations for their inclusion in Phase II/III trials, without an ESS. This could help to streamline drug development in Asia while still addressing regulatory requirements.
       
  • Multiscale modelling of drug mechanism and safety
    • Abstract: Publication date: Available online 30 December 2019Source: Drug Discovery TodayAuthor(s): Jitao David Zhang, Lisa Sach-Peltason, Christian Kramer, Ken Wang, Martin EbelingHere, we introduce models at three levels (molecular level, cellular and omics level, and organ and system level) that study drug mechanism and safety in preclinical drug discovery. The models differ in both their scope of study and technical details, but are all rooted in mathematical descriptions of complex biological systems, and all require informatics tools that handle large-volume, heterogeneous, and noisy data. We present principles and recent developments with examples at each level, and highlight the synergy by a case study. We proffer a multiscale modelling view of drug discovery, call for a seamless flow of information in the form of models, and examine potential impacts.
       
  • Anthelmintics in the future: current trends in the discovery and
           development of new drugs against gastrointestinal nematodes
    • Abstract: Publication date: Available online 26 December 2019Source: Drug Discovery TodayAuthor(s): Markéta Zajíčková, Linh Thuy Nguyen, Lenka Skálová, Lucie Raisová Stuchlíková, Petra MatouškováThe control of gastrointestinal nematodes (GINs), the most abundant and serious parasites of livestock, has become difficult because of the limited number of available drugs and fast development of drug resistance. Thus, considerable efforts have been devoted to developing new anthelmintics that are efficient against nematodes, especially resistant species. Here, we summarize the most recent results using various approaches: target-based or high-throughput screening (HTS) of compound libraries; the synthesis of new derivatives or new combinations of current anthelmintics; the repurposing of drugs currently approved for other indications; and lastly, the identification of active plant products. We also evaluate the advantages and disadvantages of each of these approaches.Graphical abstractGraphical abstract for this article
       
  • Regulatory aspects and quality controls of polymer-based parenteral
           long-acting drug products: the challenge of approving copies
    • Abstract: Publication date: Available online 26 December 2019Source: Drug Discovery TodayAuthor(s): Francesca Selmin, Umberto M. Musazzi, Giulia Magri, Paolo Rocco, Francesco Cilurzo, Paola MinghettiTo assure the safety and the efficacy of a medicinal product, quality and batch-to-batch reproducibility need to be guaranteed. In the case of parenteral long-acting products, the European Union (EU) and US Regulatory Authorities provide different indications, from the classification to the in vitro release assays related to such products. Despite their relevance, there are few in vitro experimental set-ups enabling researchers to discriminate among products with different in vivo behavior. Consequently, most copies are authorized through hybrid instead of generic applications. Here, we review the actual regulatory frameworks to evaluate the in vitro release tests of polymer-based long-acting parenterals to highlights the directions followed by the Regulatory Agencies in the USA and EU.
       
  • Evolving nanoformulation strategies for diagnosis and clinical
           interventions for Parkinson’s disease
    • Abstract: Publication date: Available online 23 December 2019Source: Drug Discovery TodayAuthor(s): Sunita Chawla, Dnyaneshwar Kalyane, Vishakha Tambe, Pran Kishore Deb, Kiran Kalia, Rakesh K. TekadeParkinson’s disease (PD) is the most common neurodegenerative disease and is associated with a loss of dopaminergic neurons in the substantia nigra. Currently available treatments provide only symptomatic relief and there is no proper diagnosis tool to detect early stages of PD. Recently, nanomedicines and nanoformulation strategies have been widely adopted for the diagnosis and treatment of PD owing to their ability to improve treatment efficacy and provide unique diagnostic functions. Furthermore, advances in nanomedicine limit the potential side effects associated with conventional therapy and provide targeted drug delivery. The objective of this review is to discuss nanoformulation strategies used for the treatment as well as the diagnosis of PD.
       
  • Fragment-based drug discovery using cryo-EM
    • Abstract: Publication date: Available online 23 December 2019Source: Drug Discovery TodayAuthor(s): Michael Saur, Michael J. Hartshorn, Jing Dong, Judith Reeks, Gabor Bunkoczi, Harren Jhoti, Pamela A. WilliamsRecent advances in cryo-electron microscopy (EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system β-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).
       
  • Corrigendum to “NCp7: targeting a multitask protein for next-generation
           anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid
           binders” [Drug Discov. Today 23(2018) 687–695]
    • Abstract: Publication date: Available online 17 December 2019Source: Drug Discovery TodayAuthor(s): Nunzio Iraci, Oriana Tabarrini, Claudio Santi, Luca Sancineto
       
  • Targeting heme-oxidized soluble guanylate cyclase to promote osteoblast
           function
    • Abstract: Publication date: Available online 14 December 2019Source: Drug Discovery TodayAuthor(s): Belay TesfamariamThe enzyme soluble guanylate cyclase (sGC) plays an essential part in the nitric oxide (NO) signaling pathway by binding to the prosthetic heme group; thereby catalyzing the synthesis of cyclic guanosine monophosphate (cGMP)-dependent protein kinases. Impaired NO-sGC-cGMP signaling could lead to osteoblast apoptosis by mechanisms involving the oxidative-stress-induced shift of the redox state of the reduced heme to oxidized sGC, leading to diminished heme binding to the enzyme and rendering the sGC unresponsive to NO. Targeting oxidized sGC to enhance cGMP production could restore proliferation and differentiation of osteoblasts into osteocytes. Here, the potential role of sGC activators of an oxidized or heme-free sGC as a target for promoting osteoblast function is reviewed and strategies for delivering drugs to bone are identified.
       
  • Comparison of DNA and mRNA vaccines against cancer
    • Abstract: Publication date: Available online 13 December 2019Source: Drug Discovery TodayAuthor(s): Zohreh Jahanafrooz, Behzad Baradaran, Jafar Mosafer, Mahmoud Hashemzaei, Tayebeh Rezaei, Ahad Mokhtarzadeh, Michael R. HamblinNucleic acid vaccines (NAVs) have recently been tested as a cancer therapy. DNA and mRNA vaccines deliver genetic information encoding tumor antigens (TAs) to the host, which then produces immune responses against cancer cells that express the TAs. Although NAVs are easy, safe, and simple to manufacture, they have not so far been considered viable alternatives to peptide vaccines. Choosing the right TAs, insufficient immunogenicity, and the immunosuppressive nature of cancer are some challenges to this approach. In this review, we discuss approaches that been used to improve the efficiency of anticancer NAVs.
       
  • ROCK-2-selective targeting and its therapeutic outcomes
    • Abstract: Publication date: Available online 12 December 2019Source: Drug Discovery TodayAuthor(s): Prasanti Sharma, Kalyan RoyDespite the identification of distinct isoforms of Rho-kinase (ROCK-1 and ROCK-2), their isoform-specific roles in several disorders remain obscure. Recent studies have revealed a vital role of ROCK-2 in various vascular and neuronal disorders, where the potential for disease alleviation is wider with ROCK-2-selective targeting than with nonspecific ROCK inhibition. This approach is also crucial for resolving issues of safety and specificity associated with nonspecific ROCK inhibitors. In this review, we focus on the latest developments concerning ROCK-2 as a therapeutic target and justify the clinical use of ROCK-2-selective inhibitors.
       
  • Cell-based immunomodulatory therapy approaches for type 1 diabetes
           mellitus
    • Abstract: Publication date: Available online 12 December 2019Source: Drug Discovery TodayAuthor(s): Labe Black, Tatiana ZorinaPhysiologically sufficient β cell regeneration can be achieved by the induction of hematopoietic chimerism in a type 1 diabetes mellitus (T1DM) mouse model. However, pancytopenia and graft-versus-host disease (GVHD) limits the clinical adaptation of this modality. In this review, we discuss new perceptions on the induction of chimerism, without bone marrow (BM) recipient conditioning, via supplementation of mesenchymal stem cells (MSCs) to support engraftment of allogeneic HSCs. The use of haploidentical, gender-matched, predisposing T1DM genotype-free HSCs in combination with MHC-disparate MSCs could lead to the development of a safe protocol for the induction of hematopoietic chimerism for the treatment of T1DM.
       
  • Targeting CDK2 in cancer: challenges and opportunities for therapy
    • Abstract: Publication date: Available online 10 December 2019Source: Drug Discovery TodayAuthor(s): Solomon Tadesse, Abel T. Anshabo, Neil Portman, Elgene Lim, Wayne Tilley, C. Elizabeth Caldon, Shudong WangCyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation. CDK2 and its regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.Graphical abstractGraphical abstract for this article
       
  • Schrödinger’s pipeline and the outsourcing of pharmaceutical
           innovation
    • Abstract: Publication date: Available online 10 December 2019Source: Drug Discovery TodayAuthor(s): Peter McMeekin, Dennis W. Lendrem, B. Clare Lendrem, Arthur G. Pratt, Richard Peck, John D. Isaacs, David JonesIn the wake of the Global Financial Crisis (2007–2008) cheaper, softer money flooded the worldwide markets. Faced with historically low capital costs, the pharmaceutical industry chose to pay down debt through share buybacks rather than invest in research and development (R&D). Instead, the industry explored new R&D models for open innovation, such as open-sourcing, crowd-sourcing, public–private partnerships, innovation centres, Science Parks, and the wholesale outsourcing of pharmaceutical R&D. However, economic Greater Fool Theory suggests that outsourcing R&D was never likely to increase innovation. Ten years on, the period of cheaper and softer money is coming to an end. So how are things looking' And what happens next'
       
  • Synthetic lethality: a step forward for personalized medicine in cancer
    • Abstract: Publication date: Available online 4 December 2019Source: Drug Discovery TodayAuthor(s): Heena Jariyal, Frank Weinberg, Abhinav Achreja, Deepak Nagarath, Akshay SrivastavaSynthetic lethality occurs between two genes when silencing of either gene alone enables viable outcomes but inhibition of both is lethal. Understanding context-dependent functioning of synthetic lethality allows therapeutic targeting in cancer. Furthermore, the paradigm shift toward precision medicine to treat cancer necessitates the establishment of biomarkers to help determine which patient populations might respond to specific drug combinations. Elucidating synthetically lethal gene combinations in cancer could establish clinically relevant drug combinations as well as biomarkers to better treat patients. Here, we have reviewed the recent synthetically lethal gene combinations in preclinical and clinical settings and discuss how this approach could help reveal potential biomarkers.
       
  • Pharmacotherapy for metabolic and cellular stress in degenerative retinal
           diseases
    • Abstract: Publication date: Available online 3 December 2019Source: Drug Discovery TodayAuthor(s): Ryo Kubota, Jeff Gregory, Susan Henry, Nathan L. MataRetinal photoreceptors continually endure stresses associated with prolonged light exposure and the metabolic demands of dark adaptation. Although healthy photoreceptors are able to withstand these stresses for several decades, the disease-affected retina functions at a reduced capacity and is at an increased risk for dysfunction. To alleviate cellular and metabolic stressors in degenerative retinal diseases, a new class of drugs that modulate the metabolic activity of the retina have been developed. A clinical candidate in this class (emixustat) has been shown to reduce retinal pathology in various animal models of human retinal disease and is currently under clinical study. Here, we describe the pharmacological properties of emixustat, its mechanisms of action, and potential for use in the treatment of specific retinal diseases.
       
  • Soft drugs for dermatological applications: recent trends
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Silvio Aprile, Marta Serafini, Tracey PiraliA soft drug (SD) displays a metabolically labile spot and, after having exerted its activity in the site of action, undergoes a fast metabolism, leading to inactive metabolites. The SD approach has recently found widespread application in the dermatological field because it provides a means of localising the therapeutic effect in skin, while minimising systemic exposure. The literature is rapidly growing of successful examples of compounds targeting sphingosine-1-phosphate receptor 1 (S1PR1), transient receptor potential vanilloid 1 (TRPV1), Janus kinase (JAK), caspase 1, and histone deacetylase (HDAC), for the treatment of skin inflammatory, autoimmune, and oncological diseases. As a demonstration of the potential of this strategy, the SD approach recently led to the approval of crisaborole, a soft phosphodiesterase 4 (PDE4) inhibitor, for atopic dermatitis, while other agents are in clinical development.
       
  • The NCATS Pharmaceutical Collection: a 10-year update
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Ruili Huang, Hu Zhu, Paul Shinn, Deborah Ngan, Lin Ye, Ashish Thakur, Gurmit Grewal, Tongan Zhao, Noel Southall, Mathew D. Hall, Anton Simeonov, Christopher P. AustinThe National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (NPC), a comprehensive collection of clinically approved drugs, was made a public resource in 2011. Over the past decade, the NPC has been systematically profiled for activity across an array of pathways and disease models, generating an unparalleled amount of data. These data have not only enabled the identification of new repurposing candidates with several in clinical trials, but also uncovered new biological insights into drug targets and disease mechanisms. This retrospective provides an update on the NPC in terms of both successes and lessons learned. We also report our efforts in bringing the NPC up-to-date with drugs approved in recent years.
       
  • Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for
           cognitive, behavioural, and psychological symptoms in psychiatric and
           neurological disorders
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Daniel Erskine, John-Paul Taylor, Geor Bakker, Alastair J.H. Brown, Tim Tasker, Pradeep J. NathanCholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.
       
  • Can BDDCS illuminate targets in drug design'
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Giovanni Bocci, Leslie Z. Benet, Tudor I. OpreaThe fact that pharmacokinetic (PK) properties of drugs influence their interaction with protein targets is a principle known for decades. The same cannot be said for the opposite, namely that targets influence the PK properties of drugs. Evidence confirming this possibility is introduced here for the first time, as we show that certain protein families have a clear preference for drugs with specific PK properties. We investigate this by cross-referencing ‘druggable target’ annotations for>1000 US Food and Drug Administration (FDA)-approved drugs with their PK profile, as defined by the Biopharmaceutics Drug Disposition Classification System (BDDCS) criteria, and then examine the BDDCS preference for several major target protein families and therapeutic categories. Our findings suggest a novel way to conduct drug discovery by focusing PK profiles at the very early stage of target selection.
       
  • Applying synergy metrics to combination screening data: agreements,
           disagreements and pitfalls
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Anna H.C. Vlot, Natália Aniceto, Michael P. Menden, Gudrun Ulrich-Merzenich, Andreas BenderSynergistic drug combinations are commonly sought to overcome monotherapy resistance in cancer treatment. To identify such combinations, high-throughput cancer cell line combination screens are performed; and synergy is quantified using competing models based on fundamentally different assumptions. Here, we compare the behaviour of four synergy models, namely Loewe additivity, Bliss independence, highest single agent and zero interaction potency, using the Merck oncology combination screen. We evaluate agreements and disagreements between the models and investigate putative artefacts of each model’s assumptions. Despite at least moderate concordance between scores (Pearson’s r>0.32, Spearman’s ρ > 0.34), multiple instances of strong disagreement were observed. Those disagreements are driven by, among others, large differences in tested concentrations, maximum response values and median effective concentrations.
       
  • Moving beyond the current limits of data analysis in longevity and healthy
           lifespan studies
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Wilson Wen Bin Goh, Subhash Thalappilly, Guillaume ThibaultLiving longer with sustainable quality of life is becoming increasingly important in aging populations. Understanding associative biological mechanisms have proven daunting, because of multigenicity and population heterogeneity. Although Big Data and Artificial Intelligence (AI) could help, naïve adoption is ill advised. We hold the view that model organisms are better suited for big-data analytics but might lack relevance because they do not immediately reflect the human condition. Resolving this hurdle and bridging the human–model organism gap will require some finesse. This includes improving signal:noise ratios by appropriate contextualization of high-throughput data, establishing consistency across multiple high-throughput platforms, and adopting supporting technologies that provide useful in silico and in vivo validation strategies.
       
  • In vivo imaging of TGFβ signalling components using positron
           emission tomography
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Lonneke Rotteveel, Alex J. Poot, Harm Jan Bogaard, Peter ten Dijke, Adriaan A. Lammertsma, Albert D. WindhorstThe transforming growth factor β (TGFβ) family of cytokines achieves homeostasis through a careful balance and crosstalk with complex signalling pathways. Inappropriate activation or inhibition of this pathway and mutations in its components are related to diseases such as cancer, vascular diseases, and developmental disorders. Quantitative imaging of expression levels of key regulators within this pathway using positron emission tomography (PET) can provide insights into the role of this pathway in vivo, providing information on underlying pathophysiological processes. PET imaging can also be used to study the drug targeting of this pathway and to detect diseases in which this pathway is disturbed. In this review, we provide an overview of PET tracers available to study the TGFβ signalling pathway. In addition, we discuss future imaging targets for this pathway and possible leads for new PET tracers.
       
  • ER stress response mediates diabetic microvascular complications
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Himanshu Sankrityayan, Manisha J. Oza, Yogesh A. Kulkarni, Shrikant R. Mulay, Anil Bhanudas GaikwadEndoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS.
       
  • Epigenetic role of thymoquinone: impact on cellular mechanism and cancer
           therapeutics
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Md. Asaduzzaman Khan, Mousumi Tania, Junjiang FuThymoquinone is a natural product known for its anticancer activity. Preclinical studies indicated numerous mechanisms of action by which thymoquinone exerts its effects on cancer cells. Recent evidence has indicated that thymoquinone can modulate epigenetic machinery, like modifying histone acetylation and deacetylation, DNA methylation and demethylation, which are among the major epigenetic changes that can contribute to carcinogenesis. Moreover, thymoquinone can alter the genetic expression of various noncoding RNAs, such as miRNA and lncRNA, which are the key parts of cellular epigenetics. This review focuses on cellular epigenetic systems, epigenetic changes responsible for cancer and the counteraction of thymoquinone to target epigenetic challenges, which might be among the mechanisms of the thymoquinone effect in cancer cells.
       
  • Early Access to Medicines Scheme: real-world data collection
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Hok Pang, Meng Wang, Christopher Kiff, Mira Soni, Dara Stein, David TyasReal-world data (RWD) generated during the pre-approval phase could be supplementary to primary clinical trial outcomes; however, as we discuss here, a data collection framework is needed to ensure the validity and applicability of these data.
       
  • Superbugs but no drugs: steps in averting a post-antibiotic era
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Mohamad Hamad, Farah Al-Marzooq, Gorka Orive, Taleb H. Al-Tel
       
  • Contents page 2
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s):
       
  • Contents page 1
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s):
       
  • Allosteric inhibition of HIF-2α as a novel therapy for clear cell
           renal cell carcinoma
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Yancheng Yu, Quanwei Yu, Xiaojin ZhangClear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and bears a significantly high frequency of hypoxia-inducible factor 2α (HIF-2α) because of von Hippel-Lindau (VHL) tumor suppressor gene mutations. From the first discovery of HIF-2α inhibitors to the promising potency of the HIF-2α inhibitor PT2977 in a clinical Phase II trial for the treatment of advanced RCC, inhibition of HIF-2α has proved to be a novel and effective therapy for RCC. In this review, we briefly discuss the role of HIF-2α in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2α allosteric inhibitors.Graphical abstractGraphical abstract for this article
       
  • DNA methyltransferases: emerging targets for the discovery of inhibitors
           as potent anticancer drugs
    • Abstract: Publication date: December 2019Source: Drug Discovery Today, Volume 24, Issue 12Author(s): Jie Yu, Tianli Xie, Zhe Wang, Xuwen Wang, Su Zeng, Yu Kang, Tingjun HouDNA methyltransferases (DNMTs) are a conserved family of cytosine methylases with crucial roles in epigenetic regulation. They have been considered as promising therapeutic targets for the epigenetic treatment of cancer. Therefore, DNMT inhibitors (DNMTis) have attracted considerable interest in recent years for the modulation of the aberrant DNA methylation pattern in a reversible way. In this review, we provide a structure-based overview of the therapeutic importance of DNMTs against different cancer types, and then summarize recently investigated DNMTis as well as their inhibitory mechanisms, focusing on recent advances in the development of DNMTis with specificity and/or selectivity using computational approaches.
       
  • Building the case for developing a medical affairs patient-centric
           framework collaboratively
    • Abstract: Publication date: Available online 29 November 2019Source: Drug Discovery TodayAuthor(s): Rebecca Ashkenazy
       
  • Antimicrobial peptides as novel therapeutics for nonsmall cell lung cancer
    • Abstract: Publication date: Available online 29 November 2019Source: Drug Discovery TodayAuthor(s): Nitesh K. KundaLung cancer is the second most common cancer in both men and women. Of all the lung cancer cases reported, 85% are nonsmall cell lung cancer (NSCLC). Although current treatments have improved the overall survival rate, success is limited, with serious treatment-related adverse effects reported. In addition, an increase in drug-resistant cancer cells limits the available treatment options. Antimicrobial peptides (AMPs) have gained much interest as anticancer drugs because they can selectively kill cancer cells but not healthy cells. Moreover, AMPs show minimal toxicity and minimal chances for developing resistance. In this review, I discuss the advantages of AMPs, their mechanism of action, and progress in AMP development for use in NSCLC treatment.
       
  • CNS organoids: an innovative tool for neurological disease modeling and
           drug neurotoxicity screening
    • Abstract: Publication date: Available online 26 November 2019Source: Drug Discovery TodayAuthor(s): Tanya Chhibber, Sounak Bagchi, Behnaz Lahooti, Angela Verma, Abraham Al-Ahmed, Manash K. Paul, Gurudutt Pendyala, Rahul Dev JayantThe paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.
       
  • Holistic cost-effectiveness analysis of anticancer drug regimens in Japan
    • Abstract: Publication date: Available online 26 November 2019Source: Drug Discovery TodayAuthor(s): Fumio Teramae, Naoya Yamaguchi, Tomohiro Makino, Shintaro Sengoku, Kota KodamaJapan officially introduced cost-effectiveness analysis (CEA) in 2019, whereas some countries, such as England, Sweden, Canada, and Australia, have experience with health technology assessment (HTA). Therefore, there are few reports that comprehensively examine the situation of health economic evaluation in Japan. In this paper, we review the health economic evaluation systems among those countries. We also conducted a case study that investigated the time-trend of cost, effectiveness, and incremental cost-effectiveness ratio (ICER) for anticancer drug regimens in Japan. We found a time-trend ICER for breast cancer (BC). Additionally, molecular targeting drugs for BC had a positive effect on the ICER, and both small molecular-targeting drugs and monoclonal antibodies (mAb) had a higher ICER for BC compared with conventional drugs. Finally, we discuss a possible way to implement a health economic evaluation system in Japan.
       
  • New-generation drugs for treatment of multiple myeloma
    • Abstract: Publication date: Available online 22 November 2019Source: Drug Discovery TodayAuthor(s): Fehaid Alanazi, Faith A.A. Kwa, Genia Burchall, Denise E. JacksonMultiple myeloma (MM), a plasma cell malignancy, is characterized by lesions in multiple bones involving transformed, matured post-follicular B cells. The course of the disease involves an initial development of monoclonal gammopathy of undetermined significance (MGUS), followed by smoldering MM, before the full MM disease emerges. Despite novel therapies, MM remains incurable, managed by combination therapies, including proteasome inhibitors (PIs), immunomodulators (IMiDs) and anti-human CD38 (daratumumab). MM patients have an increased risk of thromboembolic events owing to combination treatments with IMiDs, PIs and anti-human CD38 antibody, and steroids. This review will examine the efficacy and prothrombotic effects of MM therapies.
       
  • Bioactive modulators targeting STING adaptor in cGAS-STING pathway
    • Abstract: Publication date: Available online 20 November 2019Source: Drug Discovery TodayAuthor(s): Xi Feng, Dongyu Liu, Zhiyu Li, Jinlei BianThe cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-pathway triggers innate immune responses by recognizing cytosolic DNA. Recent studies revealed that STING adaptor associates with various diseases, and several modulators targeting STING have been identified including three agonists that have entered clinical trials for treating cancer over the past 2 years. In particular, the efficacy of STING agonists and/or antagonists suggests adaptor STING as a potential therapeutic target for diverse diseases. Herein, we summarize the latest advances in understanding STING functioning and provide an overview of recent STING modulator discoveries, including structural details and the potential therapeutic applications of these modulators.
       
  • Human ether-à-go-go-related potassium channel: exploring SAR to
           improve drug design
    • Abstract: Publication date: Available online 19 November 2019Source: Drug Discovery TodayAuthor(s): Maria Maddalena Cavalluzzi, Paola Imbrici, Roberta Gualdani, Angela Stefanachi, Giuseppe Felice Mangiatordi, Giovanni Lentini, Orazio NicolottihERG is best known as a primary anti-target, the inhibition of which is responsible for serious side effects. A renewed interest in hERG as a desired target, especially in oncology, was sparked because of its role in cellular proliferation and apoptosis. In this study, we survey the most recent advances regarding hERG by focusing on SAR in the attempt to elucidate, at a molecular level, off-target and on-target actions of potential hERG binders, which are highly promiscuous and largely varying in structure. Understanding the rationale behind hERG interactions and the molecular determinants of hERG activity is a real challenge and comprehension of this is of the utmost importance to prioritize compounds in early stages of drug discovery and to minimize cardiotoxicity attrition in preclinical and clinical studies.
       
  • Continuous progress in continuous manufacturing: on the road to real-time
           release
    • Abstract: Publication date: Available online 16 November 2019Source: Drug Discovery TodayAuthor(s): Loe Cameron
       
  • Immune checkpoint inhibitors: a promising anticancer therapy
    • Abstract: Publication date: Available online 15 November 2019Source: Drug Discovery TodayAuthor(s): Sima Singh, Daniel Hassan, Hibah M. Aldawsari, Nagashekhara Molugulu, Rahul Shukla, Prashant KesharwaniImmune checkpoint inhibitors (ICIs) are revolutionizing the treatment of many cancers and have demonstrated their potential as ‘cancer terminators’. However, ICI treatment also has constraints, such as its immune-related adverse events (irAEs) and therapeutic resistance. These drawbacks are gradually being overcome through better knowledge of the immune system, history of disease, duration of treatment, combinational drug regimes, adequate biomarkers, and effective patient response monitoring. In this review, we discuss the present ICI therapy landscape and its therapeutic outcomes for various diseases. We also highlight biomarkers related to the ICI response.
       
  • Validation of the epigenetic reader bromodomain-containing protein 4
           (BRD4) as a therapeutic target for treatment of airway remodeling
    • Abstract: Publication date: Available online 13 November 2019Source: Drug Discovery TodayAuthor(s): Allan R. Brasier, Jia ZhouStructural remodeling is central to the initiation and progression of many chronic lung diseases, representing an important unmet need. We examine the evidence supporting bromodomain-containing protein 4 (BRD4) as a validated biological target for treatment of airway remodeling. In epithelial cells and fibroblasts, BRD4 serves as a scaffold for chromatin remodeling complexes in active super-enhancers. In response to inflammatory stimuli, BRD4 is repositioned to innate and mesenchymal genes activating their production. Proof-of-concept studies show promising benefit of selective BRD4 inhibitors in disrupting epithelial mesenchymal transition and myofibroblast transition in diverse models of lung injury. Recent identification of biomarkers of BRD4 provides a basis for further drug development for application in viral-induced airway inflammation, COPD and interstitial lung diseases.
       
  • Introducing Project Africa GRADIENT
    • Abstract: Publication date: Available online 4 November 2019Source: Drug Discovery TodayAuthor(s): Iris Rajman, Oscar Della Pasqua, on behalf of the Joint Steering Committee Africa GRADIENT
       
 
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