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Drug discovery - Articles and news items
Presented by Dr Elad Katz, a senior scientist at AMSBIO, a new on-demand webinar explores the potential of 3D cell-based models for regenerative medicine and drug discovery…
Proteases: How naturally occurring inhibitors can facilitate small molecule drug discovery for cysteine proteases
Cysteine proteases are expressed ubiquitously in the animal and plant kingdom and are thought to play key roles in maintaining homeostasis. The aberrant function of cysteine proteases in humans are known to lead to a variety of epidermal disease states such as inflammatory skin disease. In marked contrast, the serine proteases have been most widely implicated in disease states, including hypertension, periodontisis, AIDS, thrombosis, respiratory disease, pancreatitis and cancer, and a number of their inhibitors have been approved for clinical use.
Raman spectroscopy has emerged as the preeminent analytical tool for a number of applications within drug discovery and development. Advances in the instrumentation, sensor fabrication and data analysis have enabled the wider acceptance of Raman spectroscopy. In discovery, Raman spectroscopy is used to elucidate structural activity relationships and to optimise reaction conditions and associated parameters (such as polymorph and formulation screening) that impact scale-up required for the transfer of drug compounds from discovery to development.
G protein-coupled receptors are one of the major classes of therapeutic targets for a broad range of diseases. The most commonly used assays in GPCR drug discovery measure production of second messengers such as cAMP or IP3 that are the result of activation of individual signalling pathways. Such specific assays are unable to provide a holistic view of the cell response after GPCR activation. This is now changing as label-free technologies and assays on whole cells have been developed that are unbiased towards the specific downstream pathways and capture the integrated cell response. In this mini-review, we focus on the application of one of these technologies, namely resonant waveguide grating (RWG) for measurements of dynamic mass redistribution (DMR) in intact cells upon GPCR activation. Since the technology is sensitive and non-invasive, it is applicable to most cell types, including primary cells with native receptor expression levels. We discuss how DMR assays have become an important component of GPCR drug discovery screening cascades and may have the potential to improve the ability to predict if compounds will be efficacious in vivo.
Torrey Pines Institute for Molecular Studies and InvivoSciences collaborate to accelerate drug discovery in cardiac disease…
The average cost to a major pharmaceutical company of developing a new drug is over USD 6 billion1. Herper1 observes that the pharmaceutical industry is gripped by rising failure rates and costs, and suggests that the cost of new drugs will be reduced by new technologies and deeper understanding of biology. While the objectives of drug discovery don’t change, the methods and techniques by which pharmaceutical companies, biotechs and academia discover new drugs are evolving at a significant pace – and they need to.
Drug discovery scientists are all aiming to identify compounds and candidate drugs with ‘good’ properties that are safe and efficacious, as quickly and cheaply as possible. The standard approach of the last 20 years has been to identify a single molecule disease target, and then to identify a compound that interacts with and modulates this target with high specificity. However, there is now a growing realisation that this ‘one target – one drug’ approach doesn’t work well, and that screening huge libraries of compounds against one particular property of an isolated target is an inefficient way to discover potential drugs. Much of the innovation currently seen in drug discovery methodologies seeks to access and integrate more information – about targets, compounds, and disease phenotypes – to enable a more comprehensive and holistic approach to discovering ‘good’ drug candidates. This article does not try to crystal ball-gaze deep into the future, but rather to identify those trends in the adoption of new technologies and approaches that are gaining traction now, and that can be expected to become more prevalent in the next two to three years.
Drug Discovery, Issue 6 2012 / 18 December 2012 / D. Lansing Taylor, Director, University of Pittsburgh Drug Discovery Institute and Allegheny Foundation Professor of Computational and Systems Biology, University of Pittsburgh School of Medicine
The pharmaceutical industry has experienced a decade of turbulence driven by the ‘patent cliff’ as major revenue generators are lost to generic status, coupled to the absence of a sustainable pipeline of drug candidates in development that have a good chance of being approved and launched1,2. It is generally agreed that the lowest hanging drug discovery ‘fruit’ has been harvested and the industry is addressing diseases that are more complex. The current one target, one drug discovery and development paradigm continues to exhibit more than 90 per cent attrition mainly due to the lack of success in translating preclinical efficacy and safety data into successful human trials1. It has also become clear that efficient drug discovery and development requires a deeper understanding of the complexity of human biology early in the process3. The high attrition rates increase the costs and with the science indicating that precision therapeutics will replace the blockbuster model4, the challenge of drug discovery and development is even greater. The traditional business model of pharmaceutical companies working in silos is no longer sustainable.
A new vision of strategic collaborations: However, there is a new vision where strategic collaborations between pharmaceutical companies, government agencies, venture capital-backed biotechnology companies and academic medical centres will create a new breadth of approaches that have a good chance of increasing the innovation that has been stagnant in recent years5-8. Government funding agencies are increasing the emphasis on translational research, even in a period of funding pressures.
In the journey of a molecule from its origins in a compound library to candidate drug status, a large variety of profiling must occur to define activity, selectivity, potency, adverse effects, pharmacology and in vivo efficacy. Advances in biophysical methods that can analyse drug interactions with a molecular target, a whole cell, or even ex vivo tissue have enabled many of these studies to be carried out without the need for reporter-based or ‘labelled’ assays. Label-free screening in high-throughput mode can be used as a pathway independent screening tool with whole cells, or in low-throughput mode with individual receptors to define interaction kinetics and thermodynamics. We highlight advances in optical and impedance-based biosensors, and examine their utility and suitability for various stages of the drug discovery process.
In the early to mid 20th century, drug discovery was a far more productive industry, and more drugs were launched per Pharma employee than today. The regulatory pathway that pre-empted the launch of a new drug was concise and easy to understand, and applications were dealt with expeditiously with a fraction of the supporting data required today. The process of discovery was also very different; it was driven largely by individuals in small teams who were prepared for serendipity, or by individuals with a very clear, defined hypothesis who drove rational drug design. Screening technologies could be summed up on one or two pages of a review; a dozen or so primary assays, some basic biochemistry to define ligand mode of action, perhaps some live cell work and a proof of concept demonstration in vivo…
The histone deacetylase (HDAC) class of enzyme are a group of conserved enzymes known for their ability to remove acetyl groups from lysine residues on histone tails. Since aberrant HDAC enzyme expression is observed in various diseases, there is increasing interest in finding small molecules which function as HDAC enzyme inhibitors. This article reviews the various biochemical assays available for monitoring HDAC enzyme activity that have been validated for use in High Throughput Screening. The assays referred to are compatible with standard microtitre plates (96 and 384 well format) and make use of absorbance, luminescence and fluorescence detection methods.
The histone deacetylase class of enzymes: The histone deacetylase (HDAC) class of enzymes are involved in many biological pathways and one of their best known properties is their ability to remove acetyl groups from lysine residues on amino-terminal histone tails. Thus far, 18 HDAC enzymes have been identified which are divided into zinc dependent and NAD dependent enzymes. The Class I HDAC enzymes include the zinc dependent HDACs 1, 2, 3, and 8 and consist of 350-500 amino acid residues. The Class II HDAC enzymes are also zinc dependent but are larger, consist of about 1,000 amino acid residues and are subdivided into Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDAC6 and HDAC10) enzymes. The Class I and Class II HDAC enzymes can be inhibited by trichostatin A (TSA) and this inhibitor is often used as a reference to bench-mark their assays. The Class III HDAC enzymes are the sirtuin enzymes (SIRT1-7) and are NAD-dependent. This class of enzymes is not sensitive to TSA but can be inhibited for example by nicotinamide.
The first biologic drug – infliximab (Remicade) – was launched in 1998 with initial sales of USD 500 million per annum. By 2010, Reuters’ top 10 drugs by sales included five biologics (Remicade, Enbrel, Humira, Avastin and Humira) generating around USD 34 billion in revenue, including USD 7.4 billion from Remicade1. Reuters have predicted that by 2014, these five will be joined in the top 10 by Herceptin, that their combined sales will be USD 47 billion per annum and that the three top-selling drugs in the world will be biologics1. It is fair to say then that biologics are transforming the landscape of the pharmaceutical industry – but how and why have these complex molecules achieved this?
Actually, the answer to the ‘why’ question is quite straightforward. They are safer and efficient in their target populations and their target populations are sometimes quite large and other times represent ‘new’ populations for therapy (i.e. there are no current therapeutic options for those patients). These factors combine to make biologics an attractive proposition for big Pharma.
Biologics are genetically-engineered proteins that mimic natural components of the immune system – including T-cells, interleukins, growth factors and interferons – and are highly specific for their targets.
Physiologically based pharmacokinetic (PBPK) models describe the different compartments (tissues) in the body linked via arterial and venous blood flow (Figure 1). The volume of each tissue and blood flows are available from literature data1-5 and PBPK models have been developed for many species including rat, mouse, dog, pig and human2,6,7. PBPK models can be applied to many aspects of the drug develop ment continuum, from drug discovery8 and into development including use in regulatory responses9.
PBPK modelling is becoming a tool of choice in the pharmaceutical industry for the prediction of pharmacokinetic parameters, drugdrug interactions (DDI) and tissue distribution from in vitro data. PBPK modelling was able to become a mainstream tool in the pharma – ceutical industry with advances in in vitro metabolism techniques along with the ability to predict tissue distribution parameters or Kp values for a number of classes of compounds10-13. These models usually assume that the liver and kidney are the only organs where elimination occurs and that blood flow to these organs limits the excretion rate. Recently, with advances in in vitro techniques to study transporter proteins, the input of these data in PBPK models is becoming more commonplace.
Ensuring patient safety during clinical trials is of paramount consideration with stringent monitoring built into trials (and beyond) and the design and interpretation of safety outcomes subject to a large amount of regulation. As a result, it is rare for clinical trials to produce extreme adverse drug reactions but it is also quite common for new medicines to fail in clinical testing due to unacceptable patient safety within a given indication. This is because once a new drug reaches clinical testing, its safety profile is already ‘locked in’, and clinical testing can only discover issues that already exist. The ideal way to ensure the safety of patients is to only progress new medicines into clinical testing which do not have unacceptable safety or tolerability issues. However, to reach this ideal means using learning in the clinic to influence design and development in the laboratory. In this short article, we discuss the practical challenges in doing this and in ‘translating’ patient safety observations such that they can impact on drug design and early development.
The safety of the patient is a paramount consideration during the development and clinical testing of new drugs. Early clinical trials are set up to carefully consider the safety and tolerability of new pharmaceuticals and patient monitoring for safety continues throughout the later clinical testing phases and beyond. Prior to this, new pharmaceutical agents are subjected to a battery of preclinical tests and must overcome strict safety hurdles before a single patient receives a dose.