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  • Reporter gene imaging and its role in imaging-based drug development
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-16
    Faiq A. Shaikh; E. Kurtys; O. Kubassova; D. Roettger

    Reporter 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.

  • New paradigm for expediting drug development in Asia
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-08
    Iris Rajman; Masaru Hirano; Wataru Honma; Sylvia Zhao

    Some 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.

  • Critical considerations in the formulation development of parenteral biologic drugs
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-08
    Bilikallahalli K. Muralidhara; Marcus Wong

    Biopharmaceuticals, 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.

  • The role of P2Y6R in cardiovascular diseases and recent development of P2Y6R antagonists
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-08
    Mengze Zhou; Weiwei Wang; Yehong Li; Qian Zhang; Hui Ji; Huanqiu Li; Qinghua Hu

    As 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.

  • An industrial approach towards solid dosage development for first-in-human studies: application of predictive science and lean principles
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-08
    Dhaval R. Kalaria; Keith Parker; Gavin K. Reynolds; Johanna Laru

    Tablet 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.

  • Key indicators of phase transition for clinical trials through machine learning
    Drug. Discov. Today (IF 6.880) Pub Date : 2020-01-08
    Felipe Feijoo; Michele Palopoli; Jen Bernstein; Sauleh Siddiqui; Tenley E. Albright

    A 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.

  • Anthelmintics in the future: current trends in the discovery and development of new drugs against gastrointestinal nematodes
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-26
    Markéta Zajíčková; Linh Thuy Nguyen; Lenka Skálová; Lucie Raisová Stuchlíková; Petra Matoušková
  • Regulatory aspects and quality controls of polymer-based parenteral long-acting drug products: the challenge of approving copies
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-26
    Francesca Selmin; Umberto M. Musazzi; Giulia Magri; Paolo Rocco; Francesco Cilurzo; Paola Minghetti

    To 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-23
    Sunita Chawla; Dnyaneshwar Kalyane; Vishakha Tambe; Pran Kishore Deb; Kiran Kalia; Rakesh K. Tekade

    Parkinson’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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-23
    Michael Saur; Michael J. Hartshorn; Jing Dong; Judith Reeks; Gabor Bunkoczi; Harren Jhoti; Pamela A. Williams

    Recent 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).

  • Targeting heme-oxidized soluble guanylate cyclase to promote osteoblast function
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-14
    Belay Tesfamariam

    The 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-13
    Zohreh Jahanafrooz; Behzad Baradaran; Jafar Mosafer; Mahmoud Hashemzaei; Tayebeh Rezaei; Ahad Mokhtarzadeh; Michael R Hamblin

    Nucleic 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-12
    Prasanti Sharma; Kalyan Roy

    Despite 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-12
    Labe Black; Tatiana Zorina

    Physiologically 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-10
    Solomon Tadesse, Abel T. Anshabo, Neil Portman, Elgene Lim, Wayne Tilley, C. Elizabeth Caldon, Shudong Wang
  • Schrödinger’s pipeline and the outsourcing of pharmaceutical innovation
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-10
    Peter McMeekin, Dennis W. Lendrem, B. Clare Lendrem, Arthur G. Pratt, Richard Peck, John D. Isaacs, David Jones

    In 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-04
    Heena Jariyal, Frank Weinberg, Abhinav Achreja, Deepak Nagarath, Akshay Srivastava

    Synthetic 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. Teaser Synthetic lethality has emerged as a powerful approach in developing personalized cancer medicine by targeting gain-of-function and loss-of-function mutations as well as metabolic vulnerabilities in cancer.

  • Pharmacotherapy for metabolic and cellular stress in degenerative retinal diseases
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-12-03
    Ryo Kubota, Jeff Gregory, Susan Henry, Nathan L. Mata

    Retinal 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.

  • Antimicrobial peptides as novel therapeutics for nonsmall cell lung cancer
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-29
    Nitesh K. Kunda

    Lung 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.

  • Holistic cost-effectiveness analysis of anticancer drug regimens in Japan
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-26
    Fumio Teramae, Naoya Yamaguchi, Tomohiro Makino, Shintaro Sengoku, Kota Kodama

    Japan 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.

  • CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-26
    Tanya Chhibber, Sounak Bagchi, Behnaz Lahooti, Angela Verma, Abraham Al-Ahmed, Manash K. Paul, Gurudutt Pendyala, Rahul Dev Jayant

    The 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.

  • New-generation drugs for treatment of multiple myeloma
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-22
    Fehaid Alanazi, Faith A.A. Kwa, Genia Burchall, Denise E. Jackson

    Multiple 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-20
    Xi Feng, Dongyu Liu, Zhiyu Li, Jinlei Bian

    The 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.

  • Improving the therapeutic efficiency of noncoding RNAs in cancers using targeted drug delivery systems
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-20
    Rami Alzhrani, Hashem O. Alsaab, Alex Petrovici, Ketki Bhise, Kushal Vanamala, Samaresh Sau, Matthew J. Krinock, Arun K. Iyer

    The delivery of noncoding (nc)RNA to target cancer stem cells and metastatic tumors has shown many positive outcomes, resulting in improved and more efficient treatment strategies. The success of therapeutic RNA depends solely on passing cellular barriers to reach the target site, where it binds to the mRNA of the interest. By 2018, 20 clinical trials had been initiated, most focusing on cancer and diabetes, with some progressing to Phase II clinical trials testing the safety and efficacy of small interfering (si)RNA. Many challenges limit RNA interference (RNAi) and miRNA usage in vivo; therefore, various approaches have been developed to promote ncRNA efficiency and stability. In this review, we focus on targeting the tumor microenvironment (TME) via the modification of delivery systems utilizing nanotechnology-based delivery approaches.

  • Human ether-à-go-go-related potassium channel: exploring SAR to improve drug design
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-19
    Maria Maddalena Cavalluzzi, Paola Imbrici, Roberta Gualdani, Angela Stefanachi, Giuseppe Felice Mangiatordi, Giovanni Lentini, Orazio Nicolotti

    hERG 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.

  • Target 2035: probing the human proteome
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-07-03
    Adrian J. Carter, Oliver Kraemer, Matthias Zwick, Anke Mueller-Fahrnow, Cheryl H. Arrowsmith, Aled M. Edwards

    Biomedical scientists tend to focus on only a small fraction of the proteins encoded by the human genome despite overwhelming genetic evidence that many understudied proteins are important for human disease. One of the best ways to interrogate the function of a protein and to determine its relevance as a drug target is by using a pharmacological modulator, such as a chemical probe or an antibody. If these tools were available for most human proteins, it should be possible to translate the tremendous advances in genomics into a greater understanding of human health and disease, and catalyze the creation of innovative new medicines. Target 2035 is a global federation for developing and applying new technologies with the goal of creating chemogenomic libraries, chemical probes, and/or functional antibodies for the entire proteome.

  • CDx, NGS and regulation: five perspectives from the Pistoia Alliance
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-07-12
    John Wise, Mike Furness, Stewart McWilliams, Simon Patton

    Companion diagnostics (CDx) are essential to the practice of precision medicine. Next-generation sequencing is an increasingly important tool in the development of CDx. However, for CDx to be deployed, many different biopharma industry sectors need to collaborate. This paper outlines some of the challenges and opportunities perceived by the biopharmaceutical industry, the Europe Molecular Quality Network, a regulatory agency, a notified body and a CDx service provider.

  • Regulatory sanctions for ethically relevant GCP violations
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-07-06
    Rosemarie de la Cruz Bernabe, Ghislaine J.M.W. van Thiel, Nancy S. Breekveldt, Christine C. Gispen, Johannes J.M. van Delden

    Although EU inspectors and clinical assessors are mandated to identify and act upon ethical issues, regulators lack guidance on how this can be done. Hence, we propose a four-step regulatory approach on ethically relevant GCP violation findings. The first step is identification of the ethical issue. Next is analysis [i.e., identifying the gravity (intensity or severity) and the magnitude (amount and duration) of the ethics violation as well as the responsible person(s) or entity or entities]. The third step is evaluation, (i.e., the process of deliberating to determine the significance of the ethics violation, with the intention of identifying the most reasonable sanction and/or corrective or reparative action). Last is decision-making or the process of choosing and implementing a regulatory course of action.

  • Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-06-04
    Kevin G. Chen, Pingyu Zhong, Wei Zheng, Jeffrey M. Beekman
  • Early Access to Medicines Scheme: real-world data collection
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-06-19
    Hok Pang, Meng Wang, Christopher Kiff, Mira Soni, Dara Stein, David Tyas

    Real-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.

  • Immune checkpoint inhibitors: a promising anticancer therapy
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-15
    Sima Singh, Daniel Hassan, Hibah M. Aldawsari, Nagashekhara Molugulu, Rahul Shukla, Prashant Kesharwani

    Immune 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
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-13
    Allan R. Brasier, Jia Zhou

    Structural 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.

  • Activity-based proteomic profiling: application of releasable linker in photoaffinity probes
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-07
    Jin Wang, Qinhua Chen, Yuanyuan Shan, Xiaoyan Pan, Jie Zhang

    Combining 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.

  • Enhancing the potential preclinical and clinical benefits of quercetin through novel drug delivery systems
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-07
    Rubiya Khursheed, Sachin Kumar Singh, Sheetu Wadhwa, Monica Gulati, Ankit Awasthi

    Quercetin 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.

  • A drug-likeness toolbox facilitates ADMET study in drug discovery
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-06
    Chen-Yang Jia, Jing-Yi Li, Ge-Fei Hao, Guang-Fu Yang
  • Nonclinical data supporting orphan medicinal product designations in the area of rare infectious diseases
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-05
    Maria E. Sheean, Eva Malikova, Dinah Duarte, Giuseppe Capovilla, Laura Fregonese, Matthias 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

    The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is responsible for evaluating applications for orphan designation (OMPDs) and for deciding the orphan status at the time of marketing authorization of medicines in the European Union (EU). In this review, we provide transparency regarding assessment criteria and an in-depth review of nonclinical models and data that have been used to support OMPDs. Additionally, we present a literature-based analysis of existing nonclinical models and discuss key features of nonclinical studies, which are considered crucial for the support of future OMPDs. This could not only inform future drug development in rare infectious conditions, but also indicate areas where nonclinical models are indispensable or can be made more efficient.

  • Drug-induced liver injury severity and toxicity (DILIst): binary classification of 1303 drugs by human hepatotoxicity
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-01
    Shraddha Thakkar, Ting Li, Zhichao Liu, Leihong Wu, Ruth Roberts, Weida Tong
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Mitochondrial permeability transition pore: a potential drug target for neurodegeneration.
    Drug. Discov. Today (IF 6.880) Pub Date : 2018-08-07
    Komal Kalani,Shi Fang Yan,Shirley ShiDu Yan

    The mitochondrial permeability transition pore (mPTP) has been considered a key contributor to cell death, inducing the process in several major neurodegenerative diseases. To date, the molecular nature of the mPTP remains confounding but its significance is universally acknowledged. Several targets have been screened and inhibition of mPTP has emerged as an attractive field for researchers. Nowadays, in silico-directed studies help to explore new small molecules targeting the mPTP to improve their drug-like properties and bioactivity. Here, we briefly summarize the role of mPTP in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson disease (PD), and Huntington's disease (HD), and discusses current and future potential therapeutic targets.

  • A special exception for CBD in foods and supplements?
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-07
    Patricia J Zettler,Erika Lietzan

  • Introducing Project Africa GRADIENT.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-07
    Iris Rajman,Oscar Della Pasqua,

  • Changing biotechnology dynamics - a blessing or a curse?
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-05
    Merve Memisoglu

  • Drugs, discovery, and dermatology: Renbök, research and repurposing.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-05
    Sidharth Sonthalia,Mahima Agrawal,Virendra N Sehgal,Vijay Gandhi,Kripa S Gupta

  • Synthetic biology - reimagine drug discovery.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-11-05
    Stephanie Brooking

  • Trapping endothelin-1 to hunt down cardiovascular disease?
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-10-28
    Bernhard Wernly,Christian Jung

  • The Art of Virtualizing Pharma R&D.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-07-20
    Alexander Schuhmacher,Oliver Gassmann,Michael Kuss,Markus Hinder

  • Sharpening the focus on cancer tumours.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-07-22
    Josephine Bunch

  • 更新日期:2019-11-01
  • Mind the gap! A survey of the challenges of biomarker commercialization.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-09-29
    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).

  • Distribution and licensing of drug discovery tools--NIH perspectives.
    Drug. Discov. Today (IF 6.880) Pub Date : 2003-01-28
    Steven M Ferguson,J P Kim

    Now, more than ever, drug discovery conducted at industrial or academic facilities requires rapid access to state-of-the-art research tools. Unreasonable restrictions or delays in the distribution or use of such tools can stifle new discoveries, thus limiting the development of future biomedical products. In grants and its own research programs the National Institutes of Health (NIH) is implementing its new policy to facilitate the exchanges of these tools for research discoveries and product development.

  • Target discovery using biobanks and human genetics.
    Drug. Discov. Today (IF 6.880) Pub Date : 2019-09-29
    Michael A Hicks,Claire Y C Hou,Arya Iranmehr,Krisztina Marosi,Ewen Kirkness

    Large-scale biobanks can yield unprecedented insights into our health and provide discoveries of new and potentially targetable biomarkers. Several protective loss-of-function alleles have been identified, including variants that protect against cardiovascular disease, obesity, type 2 diabetes, and asthma and allergic diseases. These alleles serve as indicators of efficacy, mimicking the effects of drugs and suggesting that inhibiting these genes could provide therapeutic benefit, as has been observed for PCSK9. We provide a context for these findings through a multifaceted review covering the use of genetics in drug discovery efforts through genome-wide and phenome-wide association studies, linking deep mutation scanning data to molecular function and highlighting some additional tools that might help in the interpretation of newly discovered variants.

  • 更新日期:2019-11-01
  • Corrigendum to 'Drug metabolism and pharmacokinetic strategies for oligonucleotide- and mRNA-based drug development' Drug Discovery Today 23 (2018) 1733-1745.
    Drug. Discov. Today (IF 6.880) Pub Date : 2018-12-12
    Shalini Andersson,Madeleine Antonsson,Marie Elebring,Rasmus Jansson-Löfmark,Lars Weidolf

  • Stratified medicine for cancer therapy.
    Drug. Discov. Today (IF 6.880) Pub Date : 2012-04-12
    Emily C Shaw,Peter W M Johnson

    As knowledge of the biological processes underlying malignant transformation becomes increasingly sophisticated, apparently similar diseases can be redefined according to the critical disrupted biological pathways and networks. The key genetic changes in most cancers can be mapped to one of a relatively few pathways, making it possible to classify tumours by their abnormal pathways and to identify potentially treatable--'druggable'--targets within these. The aim of the stratified approach to cancer therapy is to improve the effectiveness, tolerability and affordability of novel therapeutic agents.

  • Predictive in vivo animal models and translation to clinical trials.
    Drug. Discov. Today (IF 6.880) Pub Date : 2012-04-12
    Natalie Cook,Duncan I Jodrell,David A Tuveson

    Vast resources are expended during the development of new cancer therapeutics, and selection of optimal in vivo models should improve this process. Genetically engineered mouse models (GEMM) of cancer have progressively improved in technical sophistication and, accurately recapitulating the human cognate condition, have had a measureable impact on our knowledge of tumourigenesis. However, the application of GEMMs to facilitate the development of innovative therapeutic and diagnostic approaches has lagged behind. GEMMs that recapitulate human cancer offer an additional opportunity to accelerate drug development, and should complement the role of the widely used engraftment tumour models.

  • Combining imaging and pathway profiling: an alternative approach to cancer drug discovery.
    Drug. Discov. Today (IF 6.880) Pub Date : 2012-04-12
    Neil O Carragher,Valerie G Brunton,Margaret C Frame

    Conventional drug discovery strategies are typically 'target centric' based on the selection of lead compounds with optimised 'on-target' potency and selectivity profiles. However, high-attrition rates are often the result of compensatory or redundant cancer mechanisms and the fact that tumours do not find it difficult to escape inhibition of a single pathway. In this article, we highlight two emerging and complimentary technologies; namely phenotypic imaging and post-translational pathway profiling, which when combined with relevant disease models can provide pharmacodiagnostic and drug combination strategies that predict and counteract inherent and adaptive drug resistance. The implementation of such approaches at early stages of the drug discovery process enables more informed decisions on candidate drug selection and how to maximise and predict efficacy before clinical development.

  • 更新日期:2019-11-01
  • Healthy skepticism: assessing realistic model performance.
    Drug. Discov. Today (IF 6.880) Pub Date : 2009-04-03
    Scott P Brown,Steven W Muchmore,Philip J Hajduk

    Although the development of computational models to aid drug discovery has become an integral part of pharmaceutical research, the application of these models often fails to produce the expected impact on productivity. One reason for this may be that the expected performance of many models is simply not supported by the underlying data, because of often neglected effects of assay and prediction errors on the reliability of the predicted outcome. Another significant challenge to realizing the full potential of computational models is their integration into prospective medicinal chemistry campaigns. This article will analyze the impact of assay and prediction error on model quality, and explore scenarios where computational models can expect to have a significant influence on drug discovery research.

  • In silico platform for xenobiotics ADME-T pharmacological properties modeling and prediction. Part II: The body in a Hilbertian space.
    Drug. Discov. Today (IF 6.880) Pub Date : 2009-04-03
    Alexandre Jacob,Jaturong Pratuangdejkul,Sébastien Buffet,Jean-Marie Launay,Philippe Manivet

    We have broken old surviving dogmas and concepts used in computational chemistry and created an efficient in silico ADME-T pharmacological properties modeling and prediction toolbox for any xenobiotic. With the help of an innovative and pragmatic approach combining various in silico techniques, like molecular modeling, quantum chemistry and in-house developed algorithms, the interactions between drugs and those enzymes, transporters and receptors involved in their biotransformation can be studied. ADME-T pharmacological parameters can then be predicted after in vitro and in vivo validations of in silico models.

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