A new algorithm is proposed that facilitates the evaluation of this hybrid property space. Covalent inhibition has a rich history in drug discovery and continues to be a highly successful strategy for addressing diverse targets and disease areas. Here, the authors discuss the current status, the strengths and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development.
The authors describe the physicochemical properties of various cyclodextrins and the effects of substituents on these properties. Additionally, the authors discuss how cyclodextrins offer an additional tool to pharmaceutical scientists to overcome drug delivery challenges for problematic drugs 08 July In this short review, we discuss the determination of binding constants and complexation efficiency, and factors that influence the latter. We also describe the use of the complexation efficiency value to assess the stabilizing effects of various cyclodextrins 08 July This review emphasizes those multidrug co-crystals that could find potential applications in the treatment of various diseases and in the development of cost-effective hybrid therapeutics.
Cyclooxygenase-2 plays an important role in breast cancer pathogenesis, which stimulates the necessity for extensive research and development of new COX-2 inhibitors by the use of in silico, in vitro and in vivo techniques. Superoxide dismutases are not only key antioxidant enzymes but they also have important roles in cell signaling, metabolism and transcription. They are involved in cancer initiation, progression and metastasis, and are potential anticancer drug targets.
The field of proteomics has developed quickly over the past decade and its application to cancer research has considerable potential in the area of precision medicine. This Editorial deals with the issue of how industry can interest and attract the very best of new synthetic organic chemists to take up a career in medicinal chemistry in the Pharma Industry 07 June This paper provides the largest, revised drug reference list annotated and ranked by the risk for developing hepatotoxicity in humans DILIrank. We created the new DILIrank list by complementing the previously used druglabeling information together with existing evidence of clinical causality assessments.
The increased trend towards open innovation provides organisations with new 17 challenges in managing their compound collections. Herein we discuss a European, intersectoral crowdsourcing approach to innovative, high-quality compound libraries design and synthesis for high-throughput biological screening and drug discovery. Drug discovery research is a stimulating, viable and worthwhile endeavour for the undergraduate preparing for a career in industry.
Available approaches to target deconvolution can be grouped based on underlying principles and should be used in combination to exploit their complementarity in efforts toward understanding compound mechanism of action. Drug screening based on phenotype, rather than target, is currently an undervalued approach for antibody discovery. In this review, we find significant opportunities in accessing novel target space through phenotypic antibody discovery 11 February Phenotypic screening is gaining new momentum in drug discovery with the hope that this approach may revitalize drug discovery and improve the success rate of drug approval through the discovery of viable lead compounds and identification of novel drug targets 11 February This article concentrates on the current developments and uses of peptide therapeutics 19 January Bispecific antibodies bsAbs combine the functionality of two antibodies in one molecule.
Two bsAb-drugs are currently on the market one recently approved and more are in clinical development. Driven by large pharma, bsAbs are emerging as next-generation biologics. The first candidates from the promising class of small non-antibody protein scaffolds are now moving into clinical development and practice. Challenges remain, and scaffolds will need to be further tailored toward applications where they provide real advantages over established therapeutics to succeed in a rapidly evolving drug development landscape.
High-quality compound collections are a main determinant of drug discovery success. Academic and charitable drug discovery enterprises face common challenges, such as hit finding and target identification. Here, we describe our own creative solutions to these issues. The authors present a comprehensive overview of the use of crowdsourcing approaches in the pharmaceutical industry arranged within a strategic framework.
Spatio-temporal epigenetic gene regulation is essential for the proper development of the heart, and aberrant epigenetic mechanisms contribute to susceptibility to cardiovascular disease 25 September The authors describe how epigenetic aberration could represent future targets for the treatment of some eye diseases 25 September Epigenetic changes in response to prenatal stimuli may be responsible for the origin of various chronic diseases, 25 September If stem cell research is to achieve its expected potential the field needs an increase in collaboration and transparency.
This may be facilitated by the creation of standards and databases that adhere to them. Recent advances in the technologies for the construction of physical microenvironment and their implications in controlling stem cell fate are highlighted. The authors describe a statistical framework for mapping genes that control tumor responses to chemotherapeutic drugs as well as the efficacy of treatments in arresting tumor growth. This article provides a comprehensive overview of the various computational active-learning approaches and outlinetheir potential for drug discovery.
This paper focuses on machine learning approaches in the context of ligand-based virtual screening for addressing complex compound classification problems and predicting new active molecules. Exploring binding thermodynamics-selectivity relationship to aid drug design. Recent advances in the discovery and development of antibody—drug conjugates have led to FDA approvals and a rich clinical pipeline of promising new cancer therapies.
The authors examine a chain of thoughts leading to the conclusion that peptides offer tremendous untapped potential as future medicines. Recently described HCV E2 core crystallographic structures greatly improve the knowledge about this elusive protein. However, they partially disagree with immunological and functional data. This paper highlights these discrepancies and proposes an alternative structural arrangement. A comprehensive summary of small molecules inhibitors of ebola virus infection, their identification and available biological evidence 28 April Finding an efficient way to deliver drugs to specific target is crucial for clinical translation; here drugs conjugation with cell penetrating peptides, in particular with HIV-derived Tat peptide is discussed.
The drawbacks of currently used cancer chemotherapeutics have led to the development of novel anticancer agents with alternative modes of action. Compounds featuring an osmium center are a promising class of new therapeutics with widely tunable activity. This article examines methods of addressing age related reduction in mitochondrial activity 03 March This article reviews how the mitochondrial protein mitoNEET, the target of thiazolidone diones, may be a useful target for other diseases, including neurodegeneration, breast cancer, diabetes and inflammation.
This article discusses how restoring an appropriate level of mitochondrial fission might help in disease, in particular Huntington's Disease 03 March Here, we outline general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects, by discussing design principles for novel reagents and what types of reagents are popular with medicinal chemists in general 30 January In this critical review, we focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening FBS for constructing such libraries 30 January Point of view of the current state of the activity cliff phenomenon focusing on the rationale, effects and potential solutions to handle the influence of activity cliffs in drug discovery 04 December Proposing an integrative use of biomarkers for antidepressant treatment outcome bridging the gap from blockbuster medicine to personalized treatment.
All scientific disciplines, including medicinal chemistry, are the subject of a revolution as data are generated at unprecedented rates and their analysis and exploitation become increasingly fundamental to innovation 04 December In this article the author discusses how the increasing adoption of translational research is leading to novel integrated discovery nexuses that may change the landscape of drug discovery. This article discusses fundamental processes of translational research: Understanding the biological basis of human disorders; Lead generation and optimisation; Clinical testing 21 October Translating neuroscience research into new medicines is challenging, largely because of the complexity of the human brain.
The critical factors involved in this process are considered, along with the future prospects. The authors discuss the challenges in predicting allosteric sites reliably in proteins 30 September The authors discuss targeting allosteric glutamatergic receptors for the possible treatment of cns diseases, in particular schizophrenia 30 September The authors discuss the benefits of adopting an allosteric approach to perturb protein kinases, a class of molecule that is difficult to selectively modulate by other, more traditional approaches.
The authors review the implication of microenvironment on the development of 3D cell cultures for high throughput screening. The authors discuss those microenvironmental factors that characterize 3D cell cultures 12 September The authors discuss the benefits of using 3D cell cultures in the drug discovery pathway, rather than the conventional 2D approach.
Peptide Drug Discovery and Development
Many of the new, highly attractive targets being identified fit in relatively unexplored bioactive space which traditional lead generation approaches and existing compound libraries are not well placed to exploit 28 July A personal perspective on the use of molecule conformation in drug design 28 July This is the current guide for authors 25 June The unprecedented number of marketing approvals in for peptide therapeutics may be a harbinger for the innovative peptide-based drugs in the clinical pipeline.
The immune system is responsible for detecting and eliminating foreign pathogens and tumor cells, but avoiding self-recognition. Therefore, tolerance mechanisms are continuously under surveillance to retain this homeostasis. Available for near three decades, has the full potential of phage display been realized in peptide drug discovery?
A substantial proportion of information relevant to the modelling and simulation of physiological and pathophysiological processes is not available from databases but is instead present in unstructured scientific documents, such as journal articles, reviews and monographs. The zebrafish Danio rerio as an in vivo model organism offers great promise to investigate the molecular mechanisms of diverse human diseases, including cancers, because it constitutes a simple and cost effective animal model for performing some genetic alterations and large-scale experiments with high reproducibility 15 April Well before molecular target-based drug discovery became popular, phenotypic-based screening strategies were the foundation of pharmaceutical drug discovery Fig.
In the past 25 years, molecular target-based drug screening has become the main drug discovery paradigm used in both the pharmaceutical industry and in academic translational research centers. Recently, however, there appears to be renewed interest in reinventing phenotypic screens for lead discovery 15 April It is currently evident that the concept that one drug acts on a single receptor is not as effective as expected from the reductionism view of the lock and key model.
The growing evidence for polypharmacology i. This method to quantify tumor model phenotypes can be useful for cancer drug discovery by increasing the understanding of: This article summarizes preclinical and clinicalexperience with LDM chemotherapy, emphasizing the potential contribution of this new treatmentmodality to future paradigms in the systemic treatment of patients with cancer.
The identification of potent spliceosome modulators that demonstrate antitumor activity indicates that this complex may be a target for drug development 05 March We have entered the era of biologicals. Although new chemical entities are still produced and successfully reach the market, many new biological products like antibodies and their derivatives, siRNA, cytokines, enzymes and other therapeutic peptides are now being developed. Already a third of all new therapeutic products in were biologicals rather than chemical derivatives.
In this review the authors aim to summarize the possibilities to deliver anti-fibrotic agents to the fibrotic liver. They specifically focus on the use of biological products 25 February Industry experts gathered on 3—4 December in Basel for the 2nd Annual BioSafe European General Membership Meeting, where they shared experiences and insights into the nonclinical safety assessment of new biotherapeutic entities. Biologics produced by recombinant DNA technologies are generally complex, heterogeneous, and subject to a variety of modifications.
The biological efficacy, clearance, safety and immunogenicity of biologics are highly dependent on their structures. Therefore, there is a growing need for protein structural characterization, particularly during the drug discovery phase when a large number of candidates are being investigated. How best to write and publish a scientific paper 10 February This article describes how the study of a rare monogenic high bone mass disorder called sclerosteosis has provided a new insight into the regulation of bone formation.
Articular cartilage injury is a common orthopaedic problem affecting many people including children and adolescents. The main cause for cartilage defects in the knee includes acute traumatic injuries. Over , hip fractures per year can be attributed to osteoporosis, resulting in direct patient care costs of over 18 billion dollars in As the population ages, this cost is anticipated to rise to approxi- mately Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach.
In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target—one drug model to a multiple-target approach.
Here, in the context of anticancer drug screening, we review 2D and 3D culture approaches, consider the strengths and relevance of each method. We review some of the key factors thought to control drug—receptor binding kinetics at the molecular level and discuss several possible approaches for the rational design of drugs with desired binding kinetics. In this article the authors consider the different types of animals models used to test novel therapeutics and chemotherapies, and discuss the strengths and weaknesses of each in this regard.
The objective, therefore, of this brief review is to discuss the potential role of the current animal disease models for AD in drug development. This article reviews recent advances on the potential applications of transparent zebrafish embryo and adult zebrafish models in molecular oncology to investigate the specific functions of gene products and molecular pathways altered in cancer cells during the disease progression in addition to a xenotransplantation system to validate novel anticarcinogenic drugs. New technologies and approaches are beginning to emerge that could provide novel lead generation capabilities that enable access to new drug target classes 17 September This article discusses the subtle aspects of GPCR drug discovery from the medicinal chemistry perspective 17 September Emergent applications of gold catalysis have played a key role in the synthesis of biologically active molecules including a drug candidate 17 September This paper reviews the latest multi-objective methods and applications reported in the literature, specifically in quantitative structure— activity modeling, docking, de novo design and library design.
Further, the paper reports on related develop- ments in drug discovery research and advances in the multi-objective optimization field. In this review, we begin by introducing the basic principles of kinetics and thermodynamics of target—drug binding within the context of drug discovery. In addition, we present a meta-analysis of the recent literature describing the kinetic and thermodynamic resolution of successful clinical candidates with diverse mechanisms of action.
We finish by discussing the best practices in the triage and chemical optimization towards clinical candidates with maximal in vivo efficacy devoid of adverse events. Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations.
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Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions. The copper- I -catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants.
The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen bonding and dipole interactions. This paper highlights the fact that even simple atomic variations can cause drastic changes in molecular properties responsible for therapeutic advantages. This paper highlights the fact that even simple atomic variations can cause drastic changes in molecular properties responsible for therapeutic advantages 13 September This article discusses how the increasing adoption of translational research is leading to novel integrated discovery nexuses that may change the landscape of drug discovery.
This article reflects on the current status of the pharmaceutical industry and reasons for continued low productivity. The authors of this editorial take a more optimistic view: Individual parents and patients are increasingly doing more to fund, discover and develop treatments for rare and ultra-rare diseases that afflict their children, themselves or their friends. They are performing roles in business development that would be classed as entrepreneurial; and their organizational roles in driving the science in some cases are equivalent to those of principal investigators.
Spontaneous reporting is a crucial component of post-marketing drug safety surveillance despite its significant limitations. The size and complexity of some spontaneous reporting system databases represent a challenge for drug safety professionals who traditionally have relied heavily on the scientific and clinical acumen of the prepared mind. Computer algorithms that calculate statistical measures of reporting frequency for huge numbers of drug-event combinations are increasingly used to support pharamcovigilance analysts screening large spontaneous reporting system databases.
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. The pharmaceutical industry is under huge pressure to overhaul what is currently viewed as a highly inefficient operating model. Unacceptable levels of late-stage failure in clinical development remain a fundamental problem for the sector. Lack of efficacy is a major reason for candidate failure and a lack of understanding of disease biology is considered to be a key issue underpinning this problem.
There has been a recent upsurge in interest from pharmaceutical and biotechnology companies to collaborate with academic institutions, with the latter viewed as being home to research teams with in-depth biological knowledge and translational research expertise. The occurrence of drug resistance in oncology accounts for treatment failure and relapse of diverse tumor types. Cancer initiating cells display a range of self-defense systems that include almost all mechanisms of drug resistance.
Different molecular pathways and markers, identified in this malignant sub-population, are becoming targets for novel compounds and for monoclonal antibodies, which may be combined with conventional drugs. These interventions might eliminate drug-resistant cancer-initiating cells and lead to remission or cure of cancer patients. In this review Michele Markstein discusses recent shifts in the understanding of colorectal cancer as a stem cell based disease, based on findings that tie patient prognosis to the presence of cancer stem cells in colorectal tumors.
Effectively managing and optimizing the value of the patent portfolio is a major challenge for many firms, especially those in knowledge intensive industries, such as the pharmaceutical, biotechnological and chemical industry. However, insights on effective patent portfolio strategies are rare. Therefore, in this article we investigate in detail how firms successfully manage and optimize their patent portfolios to increase their overall competitiveness. We discover that successful patent portfolio management is rooted in managing the patents along their life cycles.
Based on the findings of ten case studies, we develop a holistic patent life cycle management model reflecting five distinctive phases of patent management: We conclude with how our findings can be used in practice. Most current research aimed at the discovery of epigenetic therapies adheres to the paradigm of target based drug discovery, focusing on the modulation of single enzymes involved in DNA methylation and histone modifications.
The recent discovery of promising small molecule inhibitors for a class of nonenzymatic chromatin regulators, the BET bromodomains, suggests that future drug discovery for epigenetic therapy will involve the modulation of protein—protein interactions and multi-protein complexes.
The rapid expansion of epigenetics research is fueled by the increasing understanding that epigenetic processes are critical to regulating cellular development and dysfunction of epigenetic programs is responsible for a diverse set of human pathologies, including cancer, autoimmune, and neurodegenerative diseases. The expansive set of components contributing to epigenetic disease mechanisms and the often reversible nature of epigenetic lesions provide prime opportunities for the development of novel therapeutic strategies.
As they do not catalyze a chemical transformation or process as such, their role is not enzymatic. However, this does not preclude them from being potential targets for drug discovery as their function is clearly correlated to transcriptional activity and as a class of proteins, they appear to have binding sites of sufficient definition and size to be inhibited by small molecules.
This suggests that this third class of epigenetic proteins that are involved in the interpretation of post-transla- tional marks as opposed to the creation or deletion of marks may represent attractive targets for drug discovery efforts. In this review, Juan Du, Timothy A. Cross and Huan-Xiang Zhou present an overview of recent progress in structure-based anti-influenza drug design, paying close attention to the increasing role of computation and strategies for overcoming drug resistance.
During the past decade, computational strategies have been developed to predict target mutation-induced drug resistance. Drug discovery is a challenging multi-objective problem where numerous pharmaceutically important objectives need to be adequately satisfied for a solution to be found.
The problem is characterized by vast, complex solution spaces further perplexed by the presence of conflicting objectives. Multi-objective optimization methods, designed specifically to address such problems, have been introduced to the drug discovery field over a decade ago and have steadily gained in acceptance ever since. At AstraZeneca a focus on hypothesis-driven design and the formation of drug design teams has placed a greater emphasis on collaboration in the drug discovery process. Robb and his team have created a novel software tool based on the principles of wikis and social networks to facilitate collaborative working, visual planning and incorporation of predictive science to improve design capability.
The very cytotoxic potency of therapeutic antibodies used in the fight against cancer makes their specific tumour targeting of crucial importance. Unfortunately, in practice, this is often not achieved and can lead to dangerous side-effects. A way of greatly reducing such side-effects is to make the antibodies region-specific to the areas bearing tumour. This can now be achieved by rendering them light dependent so they are only active where illuminated.
Signaling cascades initiated by Wnt lipoglycoproteins and their receptors of the Frizzled family regulate many aspects of animal development and physiology. Improper activation of this signaling promotes carcinogenic transformation and metastasis. Development of agents blocking the Wnt-Frizzled signaling is of prime interest for drug discovery.
Despite certain progress no such agents are as yet brought to the market or even to clinical trials. One reason for these delays might be the use of suboptimal readout assays. During the past decade, virtual screening has come of age. In this article, Yusuf Tanrikulu, Bjorn Kruger and Ewgenij Proschak document the evolution and maturation of virtual screening from a rather exotic, stand-alone method toward a versatile hit and lead identification technology. Virtual screening campaigns have become fully integrated into drug discovery campaigns, evenly matched and complementary to high-throughput screening HTS methods.
Monoclonal antibodies mAbs have been used successfully both in research and for clinical purposes. The possible use of protective mAbs directed against different microbial pathogens is currently being considered. The fine definition of the epitope recognized by a protective mAb is an important aspect to be considered for possible development in epitope-based vaccinology.
Unfortunately, this approach is not always feasible. Under this perspective, several surrogate epitope mapping strategies based on the use of bioinformatics have been developed. Chemokines and their receptors are highly interesting therapeutic targets for pharmaceutical and biotechnology companies. In particular, industrial development pipelines are filled with new chemokine-targeting drugs to treat inflammatory diseases and malignancies.
Their severe unrelenting symptoms have a huge impact on healthcare resources owing to frequent hospital admissions and requirement for intensive treatments. Consequently, there is an undeniable need for more effective and safer medications. Expanding knowledge of innate and adaptive immune responses is leading to the development of novel therapies for severe asthma. Targeted therapeutics such as monoclonal antibodies mAbs have proven successful as cancer drugs.
To profile products that could be marketed in the future, Janice M. Reichert and Eugen Dhimolea examined the current commercial clinical pipeline of mAb candidates for cancer. Analysis of the literature reveals many examples of US Food and Drug Administration-approved drugs that are active against multiple targets also termed promiscuity that can also be used to therapeutic advantage for repositioning for other neglected and rare diseases. In this article, Zhichao Liu et al. In this review, Julie Blatt and Seth J.
Corey explore the scope of drug repurposing in pediatric hematology oncology and in pediatrics in general. In this article Ramaiah Muthyala discusses new approaches to developing therapeutic options for orphan diseases.
- Why Every Black Woman Should Marry a Jewish Man: A Book For All Women Looking For the Perfect Alpha Male.
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- Postkoloniale Tendenzen in Deutschland (German Edition).
In this article Lilian A. Hook discusses how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain widespread adoption of stem cell technology by the pharmaceutical industry. In this article Lui et al. In this article Matthias Havenaar and Peter Hiscocks make the case that strategic alliances can fail because of how they are negotiated. Alliance contracts are often inflexible and do not allow for changes in market conditions.
In this article Michael K. This article provides new insights into the different strategy paths or business models currently being implemented by Canadian biopharma companies. Quantitative structure—activity relationship QSAR methods and related approaches have been used to investigate the molecular features that influence the absorption, distribution, metabolism, excretion and toxicity ADMET of drugs.
As the three-dimensional structures of several major ADMET proteins become available, structure-based docking-scoring computations can be carried out to complement or to go beyond QSAR studies. Applying docking-scoring methods to ADMET proteins is a challenging process because they usually have a large and flexible binding cavity; however, promising results relating to metabolizing enzymes have been reported. The number of solved X-ray structures of proteins relevant for ADMET processes of drug molecules has increased remarkably over recent years. In principle, this development offers the possibility to complement the quantitative structure—property relationship QSPR -dominated repertoire of in silico ADMET methods with protein-structure-based approaches.
However, the complex nature and the weak nonspecific ligand-binding properties of ADMET proteins take structural biology methods and current docking programs to the limit. In this article Ish Khanna reflects on the current status of the pharmaceutical industry and reasons for continued low productivity. Kruse begin by introducing the basic principles of kinetics and thermodynamics of target—drug binding within the context of drug discovery. Liposomes as pharmaceutical drug carriers were developed to increase antitumour efficacy and decrease drug toxicity. Doxorubicin HCl liposomal injection was the first liposomal encapsulated anticancer drug to receive clinical approval.
To date, virtually all traditional anticancer drugs have been encapsulated in liposomes. The early promise of boron neutron capture therapy as a method for the treatment of cancer has been inhibited by the inherent toxicity associated with therapeutically useful doses of 10B-containing pharmacophores, the need for target-tissue specificity and the challenges imposed by biological barriers.
Inhalation of drugs for both medicinal and recreational purposes has occurred for centuries. Over the past two decades, a variety of new formulation technologies and inhaler devices have been developed to repurpose drugs given by other routes of administration as superior inhalation products with improvements in safety, efficacy and convenience for patients.
In the past decade there has been a growing interest in lipid-based formulations to deliver challenging compounds such as lipophilic drugs. In this article Przemyslaw P. Stanisz review milestones, research directions and the evolution of approaches to the application of MRI to the analysis of CR systems. In this review Maarten Rotman, Thomas J.
There is increasing interest in the application of quantitative magnetic resonance imaging MRI methods to drug development, but as yet there is little standardization or best practice guidelines for its use in this context. In this article, Adam J. One of the most important unmet needs in the development of new drugs as well as the delivery and monitoring of new medicinal entities is the development of new biomarkers that can be used as surrogate endpoints to assess the therapeutic effect. Imaging, combining high-resolution spatial information with specific functional and molecular information, is making important inroads in producing such new biomarkers.
The evolving field of high content screening technologies will, however, require a rethinking of 3D cell culture adoption to ensure the next generation of cells provide relevant in vivo-like data. A new class of instruments offers an unprecedented combination of label-free detection with exquisite sensitivity to live-cell responses. These instruments can quantify G-protein-coupled receptor GPCR signaling through Gs, Gi and Gq pathways and in some cases distinguish G-protein coupling, with sensitivity high enough to detect endogenous receptors.
The three microenvironmental factors that characterize 3D cultures include: Although these factors have been studied individually, their interdependence and synergistic interactions have not been well appreciated. In this review, the authors discuss the microenvironmental cues that modulate the status of cells to yield physiologically more relevant three-dimensional 3D cell-based high throughput drug screening HTS platforms for drug discovery.
Evidence is provided to support the view that simplifying 3D cell culture platforms for HTS applications calls for identifying and validating ubiquitous three-dimensionality biomarkers. Published results from avascular tumorigenesis and early stages of inflammatory wound healing, where cells transition from a two-dimensional 2D to 3D microenvironment, conclusively report regulation by cytokines, providing the physiological basis for focusing on cytokines as potential three-dimensionality biomarkers.
The development of any stem-cell-based therapy and a potential one for deafness is no exception relies on the generation of the necessary tools: Orphan drug incentives have stimulated research into diseases with significant unmet medical need. Cooper outlines the progress of optical label-free in the drug discovery technology markets. Ye Fang outlines how label-free biosensors provide a new dimension for elucidating receptor biology and for facilitating drug discovery. Clay W Scott and Matthew F. Peters review emerging data evaluating impedance- and optical-based label-free instruments for GPCR drug discovery.
In this article Matthew A. Cooper highlights key advances in commercial label-free analysis platforms, which complement more traditional optical systems and which also enable novel assay formats for the analysis of previously intractable targets. In this article David Lane and Ted Hupp discuss the p53 gene.
The p53 gene is one of many tumour suppressors and appears to be relatively unique in its function at a nodal point as a mediator of the cellular response to changes in the microenvironment. In this article the authors outline the p53 transcriptional pathway, mutant p53 as an anti-cancer drug target and refolding of the structural class of mutant p In this article Giovanni Bottegoni et al.
In particular, they illustrate that fragment-based approaches can be particularly suited for polypharmacology, owing to the inherent promiscuous nature of fragments. In this article Fredrik N. An insightful analysis of the ligandability score, the success of HTS and entry into hit-to-lead is presented for 36 targets. Fragment-based screening FBS has become an established approach for hit identification.
Starting points identified by FBS, are small fragments that require substantial modification to become leads. As fragments are different from classical hits a process tailored for fragment evolution is required. Scores for ligand efficiency have been proposed as guides for this process. In this article the Sabine Schultes et al.
Academic, Foundation, and Industry Collaboration in Finding New Therapies
In this article Mark Whittaker et al. Futhermore, they illustrate this with examples from their own projects where they have found that information from fragments can inform the optimisation of hits identified by other means e. Here, we review the performance of chromatographic hydrophobicity measurements in a data set of GlaxoSmithKline compounds, demonstrating the advantages of the method over octanol—water partitioning and highlighting new insights for drug discovery.
The value of chromatographic measurements, versus other hydrophobicity estimates, was supported by improved relationships with solubility, permeation, cytochrome Ps, intrinsic clearance, hERG binding and promiscuity. We also observed marked differentiation of the relative influence of intrinsic and effective hydrophobicity.
The summing of hydrophobicity values plus aromatic ring count [log DpH7. This review article by Guodong Chen, Bethanne M. Goodenough, Hui Wei, David B. Wang-Iverson and Adrienne A. Tymiak describes recent developments and future trends in the characterization of protein therapeutics using mass spectrometry. In this article Alfonso Espada and Manuel Molina-Martin review capillary electrophoresis fundamentals, well-established capillary electrophoresis methodologies in drug discovery of small molecules and discuss trends that, in their opinion, might emerge in the coming years.
In this review Kawthar Bouchemal and Silvia Mazzaferro explain how to conduct ITC experiments correctly for CD—guest interactions, how to choose an accurate fitting model for the titration curve and how to interpret carefully the ITC results. Steven Zheng discuss the potential therapeutic value and issues of novel antineoplastic agents, with emphasis placed on those that have already entered clinical trials. Hibma and Paul Burn discuss recent advances in elucidating the cytoplasmic localization and function of ATM. Particular attention is given to the role of ATM in insulin signaling and Akt activation.
The potential for cytoplasmic ATM protein kinase to be an emerging therapeutic target for treating diabetes, cancer and neuronal degeneration is discussed. Aixia Yan, Liyu Wang, Shuyu Xu and Jun Xu summarize the common binding modes of Aurora-A kinase inhibitors, the hot spot residues in the binding sites and the privileged inhibitor structures. Their review of the reported chemical scaffolds of Aurora-A kinase inhibitors and their binding modes could provide a useful framework from which new design strategies for inhibitors might be assessed or developed.
In this article Fabrizio Manetti discusses the area of LIM kinases and how the development of inhibitors of these enzymes might be a successful approach to the treatment of AIDS. In this article Timothy J. Ritchie and Iain M. McLay discuss the pros and cons of medicinal chemists undertaking three-dimensional 3D computer-aided Q2 drug design CADD activities for themselves, from the viewpoint of both medicinal chemists and computational chemists. Schwab gives some insights into the general challenges and problems in the area of 3D structure and conformation generation and focuses on some available and recent software technologies and approaches applicable for this task.
In this article Daniela Schuster highlights the concept, recent applications and caveats of pharmacophore-based activity profiling. Additionally, they look at different parameters that are necessary to make the best use of these tools, and also how to gain acceptance outside the modelling community and into the regulatory arena. Sean Ekins, Antony J. Krasowski and Joel S. In this article Gautier Moroy, Virginie Y. Martiny, Philippe Vayer, Bruno O. Villoutreix and Maria A. Miteva discuss recently reported in silico studies aiming at predicting small molecules binding to ADMET-related proteins based on the knowledge of the 3D structures of these macromolecules with a special emphasis on metabolizing enzymes.
The advances in the datasets for model building and available computational models are summarized and the advantages and drawbacks of these models are outlined. Alexander Maywe et al. In this article, Torsten Hoffmann and Cheryl Bishop outline a chain of thoughts that concludes that chemistry has a wider part to play in innovative drug discovery than it is currently permitted by industry to have.
Cheshire provides evidence that suggests that modern medicinal chemists are overproductive in that they synthesise many more compounds than are required to achieve the objectives of the project.
Academic, Foundation, and Industry Collaboration in Finding New Therapies
Drug repurposing from an academic perspective; featured article from Drug Discovery Today: Therapeutic Strategies, Winter 13 February Highlight from Drug Discovery Today: Highlight from the Winter issue of Drug Discovery Today: Therapeutic Strategies 13 February This is a highlight of the Winter issue of Drug Discovery Today: A highlight of the Winter issue of Drug Discovery Today: In this article Carmel J. Pezaro, Deborah Mukherji and Johann S. De Bono review the preclinical discovery and clinical development of abiraterone acetate and outline the strategy of parallel translational research.
Neil Jones and Almut Schultz discuss how targeting cancer cell metabolism has emerged as a new area for anticancer drug discovery. Recent changes to non-clinical cancer guidelines offer a golden opportunity to expedite the translation of new anticancer drugs into the clinic. In this article Paul S. Jones and David Jones look at how these guidelines can be implemented and how they can be integrated with non-clinical and clinical study design to produce robust and safe clinical trials.
In this article Jon Travers, Swee Sharp and Paul Workman evaluate the key role of HSP 90 in enabling the functional and structural stabilisation of a host of client oncoproteins. The quality of much of the chemical structure-based data introduced to the public domain is poor.
In this review the authors have integrated parameters across clinical trials and associated genetic, gene expression and protein data. They provide examples to illustrate the utility of data integration to explore disease heterogeneity and develop predictive biomarkers. In this article, the authors describe a combination of structural informatics approaches developed to mine data extracted from existing structure knowledge bases Protein Data Bank and the GVK database with a focus on kinase ATP-binding site data. This article reviews progress in the development of computational methods, tools and databases used for organizing and extracting biological meaning from antimicrobial research.
In this review, De Ceuninck et al. The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized.
In this article Matheis et al. They integrated parameters across clinical trials and associated genetic, gene expression and protein data. They also provide examples to illustrate the utility of data integration to explore disease heterogeneity and develop predictive biomarkers. In this article Michael Nohaile discusses several areas of expertise that need to be considered for drug discovery and translational scientists to use stratification with biomarkers to improve the chances of getting medicines to patients.
Pavan K Battiprolu et al. Xiaopin Duan and Shirui Mao describe the main barriers preventing nasal insulin absorption, and special attention is given to new approaches to improve the intranasal absorption of insulin, including the application of new safe absorption enhancers and the use of appropriate delivery systems. Suen and Paul Burn discuss the preclinical and clinical data that have been accumulated to date on incretin-based therapies in type 1 diabetes and type 2 diabetes settings.
This review highlights some successes in discovery and translation of pharmacogenomic biomarkers for adverse drug events and outlines future strategies to optimize the development and clinical application of pharmacogenomic information. This article explores the exciting potential of mitochrondrial pharmacogenetics. Ribosomal RNA rRNA -targeting drugs inhibit protein synthesis and represent effective antibiotics for the treatment of infectious diseases. Stewart Bates explores how the advent of improved genomic tools has greatly hastened our understanding of the molecular pathology of diseases and how this could enable us to redefine diseases at the molecular level.
Together with improved diagnostic criteria, Bates discusses the question: Hudson and Orviska discuss the views of pharmacogenetics and gene therapy across European countries. These are the instructions to authors for submission of articles to Drug Discovery Today 13 September In the last ten years, public online databases have rapidly become trusted valuable resources upon which researchers rely for their chemical structures and data for use in cheminformatics, bioinformatics, systems biology, translational medicine and now drug repositioning or repurposing efforts.
Their utility depends on the quality of the underlying molecular structures used. Unfortunately, the quality of much of the chemical structure-based data introduced to the public domain is poor. There is an urgent need for government funded data curation to improve the quality of internet chemistry and to limit the proliferation of errors and wasted efforts. The original intent of the MMRC was to assemble a single group of core investigators who could validate preclinical models, form a central annotated tissue bank, and provide a common mechanism for rapid translation of laboratory findings into clinical trials.
As the consortium began to grow, one of the early observations was the need for common contract language to allow for rapid integration of many sites Table 1. This barrier was addressed through standard language for clinical-trial agreements. Armed with this central approach, the MMRC was ready to begin phase 1 and 2 trials of new agents or new combinations involving patients with relapsed myeloma. As of this writing, more than 70 trials have been initiated within the consortium, with substantial input and enrollment for trials sponsored by industry.
As an example, trials for the regulatory approval of both carfilzomib 26 and pomalidomide 27 with accelerated approval on the basis of phase 2 studies were led by the MMRC from both an enrollment and intellectual perspective. In addition, the initial phase 1b trials of the monoclonal antibody elotuzumab in combination with lenalidomide and dexamethasone 28 or with bortezomib and dexamethasone 29 were performed on the basis of preclinical scientific findings developed at MMRC sites, and trials were conducted by the MMRC. Although not all the trials led to drug approval, early decisions about trial initiation were made, which reduced the time and expense associated with conducting additional early-phase trials.
For example, early work with the HSP90 inhibitor ganetespib STA, which inhibits the activity of the HSP90 heat shock protein did not show much clinical activity alone or in combination with bortezomib, so further study of the drug was abandoned. In contrast, a phase 1b trial of elotuzumab in combination with lenalidomide and dexamethasone showed striking efficacy, which led to trials that resulted in FDA approval of this agent despite the lack of single-agent activity. Much of this work resulted from the team-based approach that the MMRC had established with industry, the FDA, and the MMRF to develop the most efficient pathway for approval of new treatment options for patients with multiple myeloma.
The MMRC tissue bank was established to provide genome-sequencing data needed for target discovery and risk stratification. This large data set led to the initial genome sequencing of samples obtained from patients with multiple myeloma 32 and subsequently enabled the creation of the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile CoMMpass clinical study, 33 a prospective observational study in which patients are undergoing initial and subsequent in-depth molecular profiling.
As of January , this study had enrolled more than patients and had provided findings from genomic analyses and clinical follow-up, data that are publicly available for investigators regardless of their participation in the trial or membership in the MMRC. In aggregate, the impetus for the MMRC — the need to have common tissue collection and access and to bring investigators together with clinical, laboratory, and trial experience in a rare disease — has resulted in rapid advancement of treatment options for patients.
In addition, through close interactions and roundtables with the FDA, the MMRC has been able to help advise industry on approaches for regulatory trial design, which has contributed to the approval of nine agents for the treatment of multiple myeloma during the past 15 years. At this time, ongoing challenges include the funding model for clinical trials, particularly those with expensive genomic analyses and correlative studies that are required in current drug development, as well as increasing the burden of paperwork associated with regulatory requirements, which challenges normal clinical workflow and adds to the cost of conducting trials Table 1.
Although it has been challenging to secure funds for correlative studies in the past, the current environment of precision medicine and immunotherapy has raised the interest level by industry to fund these studies. In the early s, treatment strategies for type 1 diabetes entered a new era that was catalyzed by the understanding that this disease was an autoimmune disorder resulting in selective destruction of insulin-secreting pancreatic islet beta cells.
Such findings have served as proof of concept for therapy directed at the underlying autoimmunity, even though these beneficial effects have been transient and the search for new treatments continues. Although the autoimmunity in type 1 diabetes often evolves over months or years preceding overt hyperglycemia, the clinical diagnosis of the disease corresponds to a critical period of beta-cell loss, which constitutes a window of opportunity for therapeutic intervention. However, most pharmaceutical companies have chosen not to prioritize immune therapy to prevent or to halt islet-cell damage in early type 1 diabetes in their clinical-trial portfolios, since the prevalence of the condition is only 0.
To fill this gap, an efficient translational ecosystem has been established that encompasses public advocacy, academic science, federal initiatives, and disease-related foundations, a collaboration that has enabled the conduct of numerous trials of new therapeutic agents that are designed to interrupt disease progression by blocking autoimmunity. The roles of the partners in this ecosystem are shown in Figure 1. At the core are patients with type 1 diabetes and academic networks, supported by the NIH, which provide centers for patient enrollment and clinical-trial operations, together with strong academic leadership groups responsible for study design and analysis.
Study concepts originate within the networks. Pharmaceutical companies are then invited to participate through providing drugs for testing in the trials, although the companies customarily have little role in the study design, conduct, or analysis. The use of skilled clinical sites and a prioritized ranking of experimental therapies ensure efficient and focused use of resources. An important element in enabling study enrollment is public education and advocacy, which among patients with type 1 diabetes is greatly helped by groups such as the Juvenile Diabetes Research Foundation, the American Diabetes Association, and the Helmsley Charitable Trust Table 1.
The costs of participating in studies of type 1 diabetes and paying for the associated drugs are not covered by any insurance carriers in the United States, and charitable organizations have helped to mitigate the costs by providing supplemental financial support to the networks or support for ancillary laboratory studies.
This closely integrated ecosystem is not without its challenges. Pharmaceutical companies may be reluctant to cede oversight over their experimental agents or lack incentive to pursue a so-called small market of patients with type 1 diabetes. And the research field has had additional challenges from several unsuccessful trials, although a recent example provides a case study in the utility of the collaborative partnership model. In this clinical trial, a combination of rapamycin sirolimus and interleukin-2 was administered to patients with recent-onset type 1 diabetes.
These findings were quickly publicized through professional conferences and publications, 37 which led to rapid developments in four areas. First, investigators conducted new trials of agents that were specifically designed to delete these effector cells — for example, the T1DAL trial, in which beta-cell function was preserved and hypoglycemic events were reduced.
These four advances not only corrected gaps in the field but also helped strengthen data-sharing ties among academic networks, funders, and industry Table 1. Each of these partners benefited from the linked relationships that supported coordination of the next drug-development steps and plans for new trial strategies. Instead of slowing progress, the challenges presented by the unsuccessful trial of rapamycin and interleukin-2 actually focused a coordinated redirection of partnership effort — an outcome that would not have been possible without strong relationships in the type 1 diabetes community.
As these three disease-specific examples demonstrate, collaborations among complementary partners that are focused on a common goal have helped to bridge the preclinical phase to early human research trials and led to major advances in each field. These collaborations, among different foundations, academic centers, federal agencies, industry, and advocacy groups, have accomplished this success with the goal of improving outcomes for patients.
- Not Being Kids.
- Lore macht Urlaub (German Edition)?
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For decades, a siloed mentality has hindered scientific and clinical-therapy development, but recent advances in clinical tools and science have necessitated larger collaborations. In an era of reduced federal funding for basic and preclinical research and drug development coupled with a higher bar for regulatory compliance , the challenges continue to remain daunting and require new and collaborative approaches for ongoing success.
In each of the cited cases, none of the major advances could have occurred in a timely manner if the partners had worked independently. Advocacy groups and foundations are finding creative ways to synergize the efforts of many partners to accelerate progress. Funding approaches that sustain these new models remain a challenge, but with powerful collaborations as the drivers and the success noted in these three examples, there is now precedent to continue to foster and support innovative partnerships.
Campbell of the Cystic Fibrosis Foundation for their review of an earlier version of the manuscript and D. Quinn Young of the Multiple Myeloma Research Foundation for reviewing an earlier version of the manuscript and providing data. Disclosure forms provided by the authors are available with the full text of this article at NEJM. National Center for Biotechnology Information , U. N Engl J Med. Author manuscript; available in PMC Apr Author information Copyright and License information Disclaimer. Address reprint requests to Dr. The publisher's final edited version of this article is available at N Engl J Med.
See other articles in PMC that cite the published article. Cystic Fibrosis In , the discovery of the gene that causes cystic fibrosis and the cystic fibrosis transmembrane conductance regulator CFTR protein 10 , 11 greatly increased interest within the scientific community in this life-shortening genetic disease, which affects approximately 70, patients worldwide. Open in a separate window. Examples of Three Collaborative Matrixes Shown are three matrixes that outline the key roles of each partner in the therapeutic development process, with the common goal of benefiting patients with cystic fibrosis, multiple myeloma, or type 1 diabetes.
Lack of clinical-trial expertise and infrastructure to conduct clinical trials The CFF established the Therapeutic Development Program and clinical-trial networks in the United States, which now has 82 sites; the European Cystic Fibrosis Society Clinical Trial Network hosts 43 sites in 15 countries. Limited efficacy outcome measures in young and minimally affected patients Partner-supported efforts developed better physiological techniques e.
Lack of patient and family input in clinical research process CFF established patient and family advisory groups at care centers worldwide and developed initiatives e. Lack of attention to the expectations of patients and their families The CFF developed Web-based educational programs for patients and their families at www. Limited clinical-trial enrollment because of small patient population The CFF formed a partnership with the Food and Drug Administration FDA to develop more efficient study designs that minimize study populations while ensuring patient safety; the Therapeutics Development Network TDN created a process for international study review and prioritization, in which research staff and patient representatives ensure that patients have access to the most effective trials.
Suboptimal study conduct that places patients at risk and that has a negative effect on drug development The CFF established a continuous, transparent assessment of study metrics at all TDN and Clinical Trials Network sites, including times for study initiation and enrollment and deviations from protocol; the foundation also established a data and safety monitoring board to review all TDN therapeutic trials.
Expensive infrastructure for the drug-development and clinical-trial networks, resulting in high drug costs Drug manufacturers adopted prices that reflect the clinical benefit and size of the market relative to development costs e. Lack of a centralized, annotated tissue repository necessary for preclinical and correlative studies The MMRC established a central tissue bank that now contains more than samples, with clinical follow-up leading to the genome sequencing of myeloma samples and other correlative study opportunities.
Need for more validated clinical targets developed from correlative studies The MMRC developed clinical targets with support from trials conducted by the cooperative groups, including the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B now called the Alliance. Lack of communication among partners with the FDA about the most effective study designs and end points The MMRC established a team-based approach with partners and the FDA to design more efficient study protocols and speed the development process.
Lack of common area for discussion and team-based global advances in this disease The International Myeloma Foundation and the International Myeloma Working Group established global collaborations on guidelines. High cost of sustaining infrastructure for therapeutic development Drug manufacturers continue to seek a sustainable funding model for drug development.
Rising costs of new approved agents to target this disease The MMRC and its partners encouraged a design for new trials with end points that do not lead to continuous therapy regimens; studies must show substantial clinical benefit to support drug approval and justify the additional costs to patients. Type 1 diabetes mellitus Lack of industry initiatives for immunologic therapies for this disease In the s, groups that are sponsored by the National Institutes of Health NIH — particularly, the Immune Tolerance Network ITN and T1D TrialNet — began to design, fund, and conduct proof-of-concept clinical trials of agents from partner pharmaceutical companies to catalyze clinical development.
Limited public awareness of this disease as an immunologic condition, distinct from type 2 diabetes, with opportunities for different therapies Private nonprofit organizations e. Lack of sufficiently useful measures of efficacy as clinical end points Academic networks and the NIH sponsored studies to improve the measurement of cellular, metabolic, and immunologic correlates of clinical benefit.
Need for combination therapy owing to the immunologic complexity in the disease mechanism Drug manufacturers began to provide access to investigational drugs for use in T1D trials. Requirement for thoughtful regulatory oversight for the testing of new drugs in children the preferred target group in this disease Advocacy groups and T1D research networks began to push for changes in the policies of regulatory agencies that require proof of therapeutic benefit in adults before testing in children. Need for data and sample sharing Efforts by research networks and the NIH led to the development of accessible repositories and data portals, such as the ITN TrialShare resource at www.
Higher costs for short-term biologic therapies than for insulin-replacement therapy Advocacy groups and their partners began to encourage a cost—benefit analysis that includes financial savings associated with disease remission and the avoidance of long-term complications of diabetes. Multiple Myeloma Patients with multiple myeloma, a cancer that is characterized by the growth of transformed plasma cells, present with infectious, skeletal, renal, and hematologic complications.
Type 1 Diabetes In the early s, treatment strategies for type 1 diabetes entered a new era that was catalyzed by the understanding that this disease was an autoimmune disorder resulting in selective destruction of insulin-secreting pancreatic islet beta cells. Conclusions As these three disease-specific examples demonstrate, collaborations among complementary partners that are focused on a common goal have helped to bridge the preclinical phase to early human research trials and led to major advances in each field.
Acknowledgments We thank R. Footnotes Financial disclosure Disclosure forms provided by the authors are available with the full text of this article at NEJM. Genetic basis for clinical response to CTLA-4 blockade in melanoma. The path to personalized medicine.
Venture philanthropy strategies to support translational research: National Academies Press; Identification of the cystic fibrosis gene: CFTR function and prospects for therapy. Cystic Fibrosis Mutation Database. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis.
Gene transfer for cystic fibrosis. Chloride channels as drug targets. Nat Rev Drug Discov. Vertex Pharmaceuticals and the Cystic Fibrosis Foundation: Harvard Business School Case Therapeutics development for cystic fibrosis: