Drug Discovery Today

Published by Elsevier
Print ISSN: 1359-6446
Publications
Adverse insults during intrauterine life can result in permanent changes in the physiology and metabolism of the offspring, which in turn leads to an increased risk of disease in adulthood. This is an adaptational response by the fetus to changes in the environmental signals that it receives during early life to ensure its survival and prepare itself for postnatal life. Increasing evidence suggests that the epigenetic regulation of gene expression patterns has a crucial role in the developmental programming of adult disease. This review summarizes recent studies of epigenetic mechanisms and focuses particularly on studies that explore identifiable epigenetic biomarkers in the promoters of specific disease-associated genes. Such biomarkers would enable early recognition of children who might be at risk of developing adult disease with fetal origins.
 
Lyotropic liquid crystal systems, such as reversed bicontinuous cubic and hexagonal mesophases, are attracting more and more attention because of their unique microstructures and physicochemical properties. Various bioactive molecules such as chemical drugs, peptides and proteins can be solubilized in either aqueous or oil phase and be protected from hydrolysis or oxidation. Furthermore, several studies have demonstrated sustained release of bioactive molecules from reversed cubic and hexagonal mesophases. This article gives an overview of recent advances and current status of reversed cubic and hexagonal mesophases, especially with respect to their preparation methods and applications in the field of drug delivery. In addition, potential problems and possible future research directions are highlighted.
 
The management of traumatic brain injury (TBI) is challenging and there is a need for neuroprotective therapies. A better understanding of the pathomechanism of TBI, particularly of the evolution of secondary damage, is providing targets for new approaches and selected ones in clinical development are described. Clinical trials that have been discontinued in the past for lack of efficacy or other reasons are also listed. One of the problems has been the translation of promising animal experimental results into clinically successful therapies. The complexity of sequelae of TBI requires a multifaceted approach. In addition to the investigation of drugs for neuroprotective effect in TBI, new technologies based on cell/gene therapies, biomarkers and nanobiotechnology are being employed for the integration of neuroprotection with neuroregeneration and are promising.
 
Absorption, distribution, metabolism and excretion (ADME) studies, are widely used in drug discovery to optimize the balance of properties necessary to convert leads into good medicines. However, throughput using traditional methods is now too low to support recent developments in combinatorial and library chemistry, which have generated many more molecules of interest. To the more enlightened practitioners of ADME science, this situation is generating both the problem and the solution: an opportunity is now forming, with the use of higher throughput ADME screens and computational models, to access this wide chemical diversity and to dissect out the rules that dictate a pharmacokinetic or metabolic profile. In the future we could see ADME properties designed-in from the first principles in drug design.
 
RNA interference (RNAi) has revolutionized the study of biology and offers numerous applications in basic biology as well as in drug discovery research. Since the discovery of RNAi, several tools have been developed to enable loss-of-function studies in mammalian systems. The efficacy of RNAi is dependent on specific and versatile RNAi triggers that have evolved to enable transient, stable and in-vivo applications. Recently developed genome-wide short hairpin RNA (shRNA) and microRNA-adapted short hairpin RNA (shRNAmir) libraries incorporate advances in shRNA design and molecular 'barcodes' to enable more complex RNAi screens and the opportunity to progress to more complex genetics in whole animals.
 
Several cytokines have been investigated in clinical trials, based on their potent therapeutic activity observed in animal models of cancer and other diseases. However, substantial toxicities are often reported at low doses, thus preventing escalation to therapeutically active regimens. The use of recombinant antibodies or antibody fragments as delivery vehicles promises to enhance greatly the therapeutic index of pro-inflammatory and anti-inflammatory cytokines. This review surveys preclinical and clinical data published in the field of antibody-cytokine fusions (immunocytokines). Molecular determinants (such as molecular format, valence, target antigen), which crucially contribute to immunocytokine performance in vivo, are discussed in the article, as well as recent trends for the combined use of this novel class of biopharmaceuticals with other therapeutic agents.
 
Peptide aptamers are combinatorial protein reagents that bind to target proteins with a high specificity and a strong affinity. By so doing, they can modulate the function of their cognate targets. Because peptide aptamers introduce perturbations that are similar to those caused by therapeutic molecules, their use identifies and/or validates therapeutic targets with a higher confidence level than is typically provided by methods that act upon protein expression levels. The unbiased combinatorial nature of peptide aptamers enables them to 'decorate' numerous polymorphic protein surfaces, whose biological relevance can be inferred through characterization of the peptide aptamers. Bioactive aptamers that bind druggable surfaces can be used in displacement screening assays to identify small-molecule hits to the surfaces. The peptide aptamer technology has a positive impact on drug discovery by addressing major causes of failure and by offering a seamless, cost-effective process from target validation to hit identification.
 
Current developments in basic discovery sciences have not been mirrored by the same level of progress in understanding the clinical basis of disease and ultimately the development of novel effective therapies. This can be improved by applying translational research throughout the late-stage discovery and exploratory development stages of drug development. A bi-directional dialogue between research scientists and clinicians concerning the biology of mechanism of action and clinical basis for disease will deliver biomarkers that enable drug development decisions to be made earlier and with increased confidence. Thus, we can better exploit the many targets that have been discovered through the mapping of the genome and other breakthroughs in medical sciences, such as the polyomic technologies.
 
At the single-cell level in conjunction with data-pattern analysis, high-content screening by image analysis or flow cytometry of clinical cell- or tissue-section samples provides differential molecular profiles for the personalized prediction of therapy-dependent disease progression in patients. The molecular reverse-engineering of these molecular profiles, which is the exploration of molecular pathways, backwards, to the origin of the observed molecular differentials, by systems biology has the potential to detect new drug targets in knowledge spaces, typically inaccessible to traditional hypotheses. Furthermore, predictive medicine, by cytomics in stratified patient groups, opens a new way for personalized (or individualized) medicine, as well as for the early detection of adverse drug reactions in patients.
 
The use of RNA interference (RNAi) is spreading rapidly to nearly every aspect of biomedical research. The gene silencing capability of RNAi is being used to study individual gene's biological function and role in biochemical pathways. However, the efficacy of RNAi depends upon efficient delivery of the intermediates of RNAi, short interfering RNA (siRNA) and short hairpin RNA (shRNA) oligonucleotides. The delivery challenge is even greater when the aim is to inhibit the expression of target genes in animal models. Although i n vivo delivery of siRNA is complicated and challenging, recent results are encouraging. In this review, the latest developments of in vivo delivery of siRNA and the crucial issues related to this effort are addressed.
 
T-cell-epitope mapping has emerged as one of the most powerful new drug discovery tools for a range of biomedical applications. Initially, T-cell-epitope discovery was applied to the development of vaccines for infectious diseases and cancer. T-cell-epitope-mapping applications have now expanded to include reengineering of protein therapeutics (a process now called deimmunization), as well as the fields of autoimmunity, endocrinology, allergy, transplantation and diagnostics. Research employing T-cell-epitope mapping falls within the realm of immunomics, a new field that addresses the interface between host and (pathogen) proteome, bridging informatics, genomics, proteomics, immunology and clinical medicine. This review highlights aspects of recent immunomics research that are related to the discovery of the T-cell immunome.
 
The receptorome, comprising at least 5% of the human genome, encodes receptors that mediate the physiological, pathological and therapeutic responses to a vast number of exogenous and endogenous ligands. Not surprisingly, the majority of approved medications target members of the receptorome. Several in silico and physical screening approaches have been devised to mine the receptorome efficiently for the discovery and validation of molecular targets for therapeutic drug discovery. Receptorome screening has also been used to discover, and thereby avoid, the molecular targets responsible for serious and unforeseen drug side effects.
 
'A wise use of lead discovery tactics will distinguish successful drug discovery engines.'
 
The macrolide rapamycin is used clinically to treat graft rejection and restenosis. Mammalian target of rapamycin (mTOR) is a central controller of cellular and organism growth that integrates nutrient and hormonal signals, and regulates diverse cellular processes. New studies have linked mTOR to several human diseases including cancer, diabetes, obesity, cardiovascular diseases and neurological disorders. Recent data have also revealed that mTOR is involved in the regulation of lifespan and in age-related diseases. These findings demonstrate the importance of growth control in the pathology of major diseases and overall human health, and underscore the therapeutic potential of the mTOR pathway.
 
It is generally acknowledged that a crucial event in the initiation and evolution of cancer is the acquisition of a genomic instability phenotype. This review focuses on mechanisms of chromosomal instability including aneuploidy, chromosome rearrangement and breakage-fusion-bridge cycles. The role of micronutrient deficiency, such as folate deficiency, in the causation of chromosomal instability is briefly reviewed and the concept of recommended dietary allowances for genomic stability is introduced. In addition, the techniques for measuring the various chromosomal instability events are discussed with a focus on the cytokinesis-block micronucleus assay as an almost complete system for measuring these various genetic mishaps.
 
Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11beta-HSD1 in adipose tissue. Transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11beta-HSD1 knockout mice have a 'cardioprotective' phenotype, whose effects are also seen with 11beta-HSD1 inhibitors in rodents. However, any major metabolic effects of 11beta-HSD1 inhibition in humans are, as yet, unreported. 11beta-HSD1 null mice also resist cognitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11beta-HSD1 inhibition is an emerging pleiotropic therapeutic target.
 
Microarray analyses reveal global changes in gene expression in response to environmental changes and, thus, are well suited to providing a detailed picture of bacterial responses to antibiotic treatment. These responses are represented by patterns of gene expression, termed expression signatures, which provide insight into the mechanism of action of antibiotics as well as the general physiological responses of bacteria to antibiotic-related stresses. The complexity of such signatures is challenging the notion that antibiotics act on single targets and this is consistent with the concept that there are multiple targets coupled with common stress responses. A more detailed knowledge of how known antibiotics act should reveal new strategies for antimicrobial drug discovery.
 
During the past decade we witnessed a rapid advance in the new field of chemical science, combinatorial chemistry. The pharmaceutical industries invested heavily in accelerating the development of this new technology. As a result, it has become an extremely important tool in lead identification and optimization in current pharmaceutical research. It also quickly crossed the boundaries of the original chemical discipline and demonstrated great potential in many other important areas, such as searching for novel and highly efficient catalysts and superconductive material. Researchers from both academic and industrial laboratories have directed great effort towards the development of novel strategies for combinatorial synthesis.
 
Web-based technologies, coupled with a drive for improved communication between scientists, have resulted in the proliferation of scientific opinion, data and knowledge at an ever-increasing rate. The availability of tools to host wikis and blogs has provided the necessary building blocks for scientists with only a rudimentary understanding of computer software science to communicate to the masses. This newfound freedom has the ability to speed up research and sharing of results, develop extensive collaborations, conduct science in public, and in near-real time. The technologies supporting chemistry, while immature, are fast developing to support chemical structures and reactions, analytical data support and integration to related data sources via supporting software technologies. Communication in chemistry is already witnessing a new revolution.
 
Bioinformatics has, out of necessity, become a key aspect of drug discovery in the genomic revolution, contributing to both target discovery and target validation. The author describes the role that bioinformatics has played and will continue to play in response to the waves of genome-wide data sources that have become available to the industry, including expressed sequence tags, microbial genome sequences, model organism sequences, polymorphisms, gene expression data and proteomics. However, these knowledge sources must be intelligently integrated.
 
For the past decade the pharmaceutical industry has experienced a steady decline in productivity and a striking observation is that the decline coincided with the introduction of target-based drug discovery. The target-based approach can very effectively develop novel treatments for a validated target, but the process of target validation is complex and associated with a high degree of uncertainty. The purpose of this paper is to analyse these aspects in detail to determine if weaknesses in this part of the drug discovery path might explain why this paradigm has not resulted in increased productivity over the traditional in vivo approach, considering its superiority in screening capacity and its ability to define rational drug discovery programs.
 
Data mining of available biomedical data and information has greatly boosted target discovery in the 'omics' era. Target discovery is the key step in the biomarker and drug discovery pipeline to diagnose and fight human diseases. In biomedical science, the 'target' is a broad concept ranging from molecular entities (such as genes, proteins and miRNAs) to biological phenomena (such as molecular functions, pathways and phenotypes). Within the context of biomedical science, data mining refers to a bioinformatics approach that combines biological concepts with computer tools or statistical methods that are mainly used to discover, select and prioritize targets. In response to the huge demand of data mining for target discovery in the 'omics' era, this review explicates various data mining approaches and their applications to target discovery with emphasis on text and microarray data analysis. Two emerging data mining approaches, chemogenomic data mining and proteomic data mining, are briefly introduced. Also discussed are the limitations of various data mining approaches found in the level of database integration, the quality of data annotation, sample heterogeneity and the performance of analytical and mining tools. Tentative strategies of integrating different data sources for target discovery, such as integrated text mining with high-throughput data analysis and integrated mining with pathway databases, are introduced.
 
Vaccination is one of the most effective tools for the prevention of infectious diseases. The availability of complete genome sequences, together with the progression of high-throughput technologies such as functional and structural genomics, has led to a new paradigm in vaccine development. Pan-genomic reverse vaccinology, with the comparison of sequence data from multiple isolates of the same species of a pathogen, increases the opportunity of the identification of novel vaccine candidates. Overall, the conventional empiric approach to vaccine development is being replaced by vaccine design. The recent development of synthetic genomics may provide a further opportunity to design vaccines.
 
Plant-produced vaccines are a much-hyped development of the past two decades, whose time to embrace reality may have finally come. Vaccines have been developed against viral, bacterial, parasite and allergenic antigens, for humans and for animals; a wide variety of plants have been used for stable transgenic expression as well as for transient expression via Agrobacterium tumefaciens and plant viral vectors. A great many products have shown significant immunogenicity; several have shown efficacy in target animals or in animal models. The realised potential of plant-produced vaccines is discussed, together with future prospects for production and registration.
 
Post-translational modifications, such as acetylation or phosphorylation, play a crucial role in the regulation of gene transcription in eukaryotes. Different subtypes of histone acetyl transferases (HATs) catalyze the acetylation of histones on specific lysine residues. A potential role of HATs in the pathology of cancer, asthma, COPD and viral infection has been described. This indicates that specific HAT inhibitors are potential tools for pharmacological research and might find therapeutic applications. This review focuses on the role of the HATs p300, CBP, PCAF and GCN5 in different diseases and the development of small-molecule inhibitors of these enzymes as potential drugs.
 
A convergence of different commercial and publicly accessible chemical informatics, databases and social networking tools is positioned to change the way that research collaborations are initiated, maintained and expanded, particularly in the realm of neglected diseases. A community-based platform that combines traditional drug discovery informatics with Web2.0 features in secure groups is believed to be the key to facilitating richer, instantaneous collaborations involving sensitive drug discovery data and intellectual property. Heterogeneous chemical and biological data from low-throughput or high-throughput experiments are archived, mined and then selectively shared either just securely between specifically designated colleagues or openly on the Internet in standardized formats. We will illustrate several case studies for anti-malarial research enabled by this platform, which we suggest could be easily expanded more broadly for pharmaceutical research in general.
 
PEG derivatives that maintain the charge of the native protein in the final conjugate
PEGylation defines the modification of a protein, peptide or non-peptide molecule by the linking of one or more polyethylene glycol (PEG) chains. This polymer is non-toxic, non-immunogenic, non-antigenic, highly soluble in water and FDA approved. The PEG-drug conjugates have several advantages: a prolonged residence in body, a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity. Thanks to these favorable properties, PEGylation now plays an important role in drug delivery, enhancing the potentials of peptides and proteins as therapeutic agents.
 
High content screening (HCS) has emerged as an important platform technology for early drug discovery from target identification through in vitro ADME/Tox. The focus is now on implementing multiplexed assays, developing and using advanced reagents and developing and harnessing more sophisticated informatics tools. Multiplexed HCS assays have the potential to dramatically improve the early drug discovery process by creating systems cell biology profiles on the activities of compounds. It is predicted that multiplexed HCS assays will accelerate the overall workflow and produce deeper functional knowledge, thereby permitting better decisions on what compounds to pursue.
 
Delivery of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains of the eye. There is an increasing need for managing rapidly progressing posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. Drug delivery to the posterior segment of the eye is therefore compounded by the increasing number of new therapeutic entities (e.g. oligonucleotides, aptamers and antibodies) and the need for chronic therapy. Currently, the intravitreal route is widely used to deliver therapeutic entities to the retina. However, frequent administration of drugs via this route can lead to retinal detachment, endophthalmitis and increased intraocular pressure. Various controlled delivery systems, such as biodegradable and non-biodegradable implants, liposomes and nanoparticles, have been developed to overcome such adverse effects, with some success. The periocular route is a promising alternative, owing to the large surface area and the relatively high permeability of the sclera. Yet, the blood-retinal barrier and efflux transporters hamper the transport of therapeutic entities to the retina. As such, the efficient delivery of drugs to the posterior eye remains a major challenge facing the pharmaceutical scientist. In this review, we discuss the barriers of the posterior eye drug delivery and the various drug-delivery strategies used to overcome these barriers.
 
The future of drug design and the development of new therapeutics will rely on our ability to unravel the complexities of the epigenome in normal and disease states. Proper epigenetic regulation is essential for normal differentiation in embryogenesis and development. Conversely, abnormal epigenetic regulation is a feature of complex diseases, including cancer, diabetes, heart disease and other pathologies. Epigenetic therapies hold promise for a wide range of biological applications, from cancer treatment to the establishment of induced pluripotent stem cells. The creation of more specific and effective epigenetic therapies, however, requires a more complete understanding of epigenomic landscapes. Here, we give a historical overview of the epigenomics field and how epigenetic modifications can affect embryo development and disease etiology. We also discuss the impact of current and future epigenetic drugs.
 
The genomic era has brought with it a basic change in experimentation, enabling researchers to look more comprehensively at biological systems. The sequencing of the human genome coupled with advances in automation and parallelization technologies have afforded a fundamental transformation in the drug target discovery paradigm, towards systematic whole genome and proteome analyses. In conjunction with novel proteomic techniques, genome-wide annotation of function in cellular models is possible. Overlaying data derived from whole genome sequence, expression and functional analysis will facilitate the identification of causal genes in disease and significantly streamline the target validation process. Moreover, several parallel technological advances in small molecule screening have resulted in the development of expeditious and powerful platforms for elucidating inhibitors of protein or pathway function. Conversely, high-throughput and automated systems are currently being used to identify targets of orphan small molecules. The consolidation of these emerging functional genomics and drug discovery technologies promises to reap the fruits of the genomic revolution.
 
and organelles are targeted to, and degraded by, the lysosome. Given that neurodegenerative diseases involve the production of misfolded proteins that cannot be degraded by the protein quality-control systems of the cell, the autophagy pathway is now the focus of intense scrutiny, because autophagy is primarily responsible for maintaining normal cellular proteostasis in the central nervous system (CNS). Huntington's disease (HD) is an inherited CAG-polyglutamine repeat disorder, resulting from the production and accumulation of misfoldedhuntingtin (Htt) protein. HD shares key features with common neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) and, thus, belongs to a large class of disorders known as neurodegenerative proteinopathies. Multiple independent lines of research have documented alterations in autophagy function in HD, and numerous studies have demonstrated a potential role for autophagy modulation as a therapeutic intervention. In this review, we consider the evidence for autophagy dysfunction in HD, and delineate different targets and mechanistic pathways that might account for the autophagy abnormalities detected in HD. We assess the utility of autophagy modulation as a treatment modality in HD, and suggest guidelines and caveats for future therapy development directed at the autophagy pathway in HD and related disorders.
 
Hypoxia-inducible factor 1 (HIF-1) regulates the transcription of many genes involved in key aspects of cancer biology, including immortalization, maintenance of stem cell pools, cellular dedifferentiation, genetic instability, vascularization, metabolic reprogramming, autocrine growth factor signaling, invasion/metastasis, and treatment failure. In animal models, HIF-1 overexpression is associated with increased tumor growth, vascularization, and metastasis, whereas HIF-1 loss-of-function has the opposite effect, thus validating HIF-1 as a target. In further support of this conclusion, immunohistochemical detection of HIF-1alpha overexpression in biopsy sections is a prognostic factor in many cancers. A growing number of novel anticancer agents have been shown to inhibit HIF-1 through a variety of molecular mechanisms. Determining which combination of drugs to administer to any given patient remains a major obstacle to improving cancer treatment outcomes.
 
Small, cell-permeable and target-specific chemical ligands offer great therapeutic value. They can also be used to dissect diverse biological processes, such as cellular metabolism, signal transduction and intracellular protein trafficking. With cutting-edge technologies in synthetic chemistry and ligand screening and identification, chemical ligands have become more readily available for research. Chemical ligands are used increasingly in genomics approaches to understand the global functions of proteins, an emerging frontier called 'chemical genomics'. Chemical genomics should greatly accelerate discovery in biology and medicine in the near future.
 
We review strategic approaches taken over an eight-year period at BMS to implement new high-throughput approaches to lead discovery. Investments in compound management infrastructure and chemistry library production capability allowed significant growth in the size, diversity and quality of the BMS compound collection. Screening platforms were upgraded with robust automated technology to support miniaturized assay formats, while workflows and information handling technologies were streamlined for improved performance. These technology changes drove the need for a supporting organization in which critical engineering, informatics and scientific skills were more strongly represented. Taken together, these investments led to significant improvements in speed and productivity as well a greater impact of screening campaigns on the initiation of new drug discovery programs.
 
Drug discovery is evolving at an incredible rate. Genomics is providing targets faster than we can validate them and combinatorial chemistry is providing new chemical entities faster than we can screen them. Meanwhile, engineers are developing better detection methods, better data handling, better fluidics and better robots. It has become a tremendous challenge for the modern drug-discovery-laboratory director to expend resources efficiently. New technology cannot be continually brought in-house and be instantly brought on line. To paraphrase many comments at the meeting: 'We do not have time to try out all these technologies. We have to screen targets.' This meeting provided several real success stories of how some of these new technologies have made drug discovery more efficient. To this end, the meeting was a success.
 
In this paper, we review the key solutions that enabled evolution of the lead optimization screening support process at Bristol-Myers Squibb (BMS) between 2004 and 2009. During this time, technology infrastructure investment and scientific expertise integration laid the foundations to build and tailor lead optimization screening support models across all therapeutic groups at BMS. Together, harnessing advanced screening technology platforms and expanding panel screening strategy led to a paradigm shift at BMS in supporting lead optimization screening capability. Parallel SAR and structure liability relationship (SLR) screening approaches were first and broadly introduced to empower more-rapid and -informed decisions about chemical synthesis strategy and to broaden options for identifying high-quality drug candidates during lead optimization.
 
Top-cited authors
Hartmuth C Kolb
  • Johnson & Johnson
Arun Iyer
  • Wayne State University
Torsten Hoffmann
  • Space Peptides
Sanjay Garg
  • Maharishi Markandeshwar University, Mullana
Miles Congreve
  • Isomorphic Labs