SLAS Europe 2019 Conference & Exhibition
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The SLAS Europe 2019 Conference and Exhibition course package contains 39 presentations including:
36 presentations from four scientific tracks
Advances in In Silico Drug Discovery
Advances in Experimental Drug Discovery
Advances in Laboratory Automation Technology
Careers, Business & Technology: Explore the Opportunities
Three keynote speakers
Based on presenter permission, 39 of the 61 total SLAS Europe 2019 Conference & Exhibition presentations are available on-demand.
The SLAS Scientific Program Committee selects conference speakers based on the innovation, relevance and applicability of research as well as those that best address the interests and priorities of today’s life sciences discovery and technology community. All presentations are published with the permission of the presenters.
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The Practical Challenges of Using Organoids in Cancer Drug Discovery
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Open to view video.
Organoid models have huge potential within drug discovery as they appear to be better predictors of efficacy. Using organoids derived from genetically modified mice we show that responses to inhibitors of the Wnt pathway recapitulate cancer-relevant biology better than culture-adapted cancer cell lines. We also show that the complex biology exhibited by human colorectal cancer organoids are best analysed by multiparametric imaging assays that are compatible with high throughput analysis. Our findings demonstrate that 3D culture models combined with imaging readouts may be most applicable in contexts when stem cell biology contributes to drug response phenotypes.
New Strategies Against Diabetes
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Open to view video.
Poly-pharmacological approaches to combat various aspects of metabolic diseases will be discussed.
Target Identification through Functional Genomics Using CRISPR Libraries
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Open to view video.
A review of the AstraZeneca discovery portfolio revealed that 83% of projects that close in this phase do so due to failure of the target validation hypothesis. This observation has led to investment in genomics, functional genomics and multi-omics for target identification. We have a three-part functional genomics strategy. We have created the capability to screen the whole genome arrayed CRISPR libraries to delete or upregulate the expression of every gene in the genome; in partnership with Cancer Research UK we have created the CRUK AZ Centre for Functional Genomics to perform whole genome-wide pooled CRISPR screens to identify new targets in oncology and to identify genes that mediate resistance or sensitisation to our medicines, and we have established partnerships with groups such as the Innovative Genomics Institute to explore the use of CRISPR in specific diseases. I will describe how this capability is being used to bring new targets into the AstraZeneca discovery portfolio.
A Homogeneous Bioluminescent Immunoassay Approach to Interrogate Cellular Signaling Pathways Activation and Deactivation
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Open to view video.
Immunoassays such as ELISA and Western blots are routinely used for protein detection and PTM analysis (e.g phosphorylation). Although sensitive, these methods are tedious, require multiple washing steps, and not easily adaptable to HTS. I will describe a novel bioluminescent NanoBiT cell-based immunoassay approach which takes less than two hours to complete in a homogeneous “Add and Read” format. We validated this platform by monitoring the activation of multiple signalling pathways through specific nodes of phosphorylation (e.g pIkB, pAKT, and pSTAT3). We tested different small or large molecule inhibitors of these pathways and obtained the expected pharmacology. Other advantages of this bioluminescent approach include no cell engineering as the phosphorylation of endogenous substrate is detected in any cell type. This new technology can be adapted to any signalling pathway node, allowing scientists to streamline the analysis of signalling pathways of interest during drug discovery.
Small Molecules Modulating Conformation of the Protein PDK1
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Open to view video.
Protein kinases are regulatory proteins that transmit intracellular signals. We investigated the molecular mechanism of regulation of the phosphoinositide-dependent protein kinase-1 (PDK1) and related protein kinases from the AGC group. AGC kinases have a regulatory pocket on the small lobe of the kinase domain, termed “PIF- pocket”. The binding of polypeptides to the PIF-pocket allosterically affects the ATP-binding site, increasing the kinase catalytic activity. Allostery implies that the reverse modulation, i.e. from the ATP-binding site to the interaction and regulatory sites must also be possible. Drugs developed to bind at the ATP-binding site of protein kinases can have the reverse allosteric effects at the regulatory sites, enhancing or disrupting protein kinase interactions. While “disrupting protein-protein interactions is very difficult," the industry has been unwillingly developing potent drugs that bind at the ATP-binding site and disrupt protein kinase interactions.
A Translational Approach to Measure Target and Off-target Engagement in Dosed Animals and Human Blood by Thermal Shift Assay
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Open to view video.
Thermal proteome profiling (TPP) enables the proteome-wide assessment of drug-protein interactions by combining quantitative mass spectrometry with the cellular thermal shift assay introduced in 2013 by Paer Nordlund group. TPP determines the thermal stability of the entire proteome by measuring the soluble fractions of proteins after heating cells or cell extracts to a range of temperatures. While the monitoring of drug-target interactions was established for simple cell systems, it remains challenging for more complex biological systems like tissues or whole blood. Here we introduce a method termed “tissue-TPP” to investigate proteome-wide thermal stability in tissues derived from dosed animals, thus enabling the measurement of target and off-target occupancy. We used the histone deacetylase inhibitor panobinostat as a tool. After dosing with panobinostat, we compared the thermal proteome profiles in liver, lung, kidney and spleen pieces from dosed rats using an unbiased statistical method. The majority of the panobinostat-induced effects observed in previously studied in vitro models (cell extracts, cells and tissue pieces) translated well into the in vivo system.
Also, the magnitude of the effects on targets and off-targets correlated with drug concentrations in the respective tissues.
The option to monitor target engagement in a clinical setting would allow the optimization of dosing regimens for patients to maximize therapeutic efficacy and reduce adverse effects. To enable target engagement measurements in samples readily accessible from clinical studies, we developed a thermal shift assay in whole blood, termed “blood-CETSA”. We measured the engagement of panobinostat with targets and off-targets previously identified. Thus, in clinical and pre-clinical studies, blood-CETSA could provide a quantitative measurement of target engagement after in vivo dosing. In summary, thermal proteome profiling enables the unbiased identification of drug targets and off-targets. With tissue-TPP it is possible to monitor target and off-target engagement in vivo, thus allowing to measure organ-specific effects of a drug on proteins. Finally, the blood-CETSA approach could measure drug-target engagement in blood samples from clinical studies and has the potential to impact translational research.
High-Throughput CETSA in Early Drug Discovery
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Open to view video.
Drug discovery suffers from a lack of technologies that can quantify the binding of a small molecule to the desired target in cells. Such measures of target engagement are critical to bridge the gap between binding the target and exerting the desired phenotypic effect. The Cellular Thermal Shift Assay (CETSA®) has emerged as a powerful technology to enable measures of target engagement in live cells. CETSA can be applied in a label-free manner to quantify binding to endogenously expressed proteins within disease-relevant cells. We will present the output of an evaluation of microtitre plate-based high-throughput CETSA (CETSA HT) in early drug discovery performed at AstraZeneca. Novel CETSA HT assays were developed for a number of high value oncology targets including B-Raf, PARP1 and the Androgen Receptor. We found CETSA HT screening to be robust and reliable across various aspects of hit finding, lead optimisation and mode of action studies and describe case studies where CETSA HT was applied to support high-throughput screening campaigns, to build correlative understanding across numerous assay formats when optimising chemistry, and to measure intracellular binding affinities. Our results support the use of CETSA HT as a broadly applicable and valuable methodology to help drive drug discovery campaigns to molecules that bind the intended target in cells.
Mapping Druggable Proteins Using Proteome-Wide Thermal Stability and Solubility Profiling
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Open to view video.
Many disease-causing proteins are often difficult to target using small molecule drugs. Currently, there is only a 25% overlap between the “druggable” proteins and the known disease-causing gene products. Thus, a typical drug discovery process involving screening of small molecule libraries using target-based assays or cell-based phenotypic assays is unlikely to be successful. Understanding the network of proteins and metabolites that directly influence the functions of disease-causing proteins or act as their downstream effectors, may aid in the identification of “druggable” alternative targets. Here, we elucidate the use of an unbiased mass spectrometry-based approach to map transient protein-metabolite interactions of adenosine triphosphate (ATP) and guanosine triphosphate (GTP), which provides a quantitative insight into their biological roles in cells. By measuring the thermal stability of proteins in the presence of these nucleotides, we obtain a global picture of ATP and GTP accessed proteins and protein complexes. Further, using a newly developed technology that measures protein solubility we uncover a non-canonical role of these abundant nucleotide metabolites in influencing the solubility status of the proteome. Thus, this proteome-wide regulatory landscape of ATP and GTP provides a quantitative outlook on the network of proteins that can be perturbed using small molecules of similar chemistry and a possible target space for drug discovery.
Workplaces of the Future: Future Topics and Trends for Human-Machine Interaction – Implications for Lab Automation
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Open to view video.
New trends and current research concerning interactions in highly-automated work environments.
New Developments in User Machine Interaction - AstraZeneca Approaches to Collaborative Robotics
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Open to view video.
Construction is ongoing to create the new AstraZeneca R&D headquarters at the heart of the Cambridge Biomedical Campus (UK) to co-locate all our research functions. Within this site we are creating an open porous collaboration environment, inviting the Medical Research Council, Cancer Research UK, Charles River and others to generate an industry-academic partnership in the formation of the United Kingdom Centre for Lead Discovery (UKC4LD). Through shared expertise, experience and learning, we aim to accelerate new medicines discovery across all partners. The formation of the UKC4LD provided a unique opportunity to plan and realise a multidisciplinary laboratory, enabling equal access to the most up to date scientific infrastructure for early phase small molecule discovery. We will review how we selected and optimised the new generation of collaborative robots, designing human “friendly” equipment that can be directly addressed from the scientist’s perspective without the need for restrictive safety guarding. We partnered with HighRes Biosolutions to develop a new concept for modular reconfigurable automation to meet our varied small molecule screening demand, establishing the range of CoLAB products. We will discuss the benefits of our mobile automation approach, and how in addition to the hardware, the scheduling software has been evolved to maximize benefit to assay performance and system reliability. In conclusion, we will review our experience to date with both internal and external projects performed across the CoLAB Flex carts and larger combined CoLAB platforms, summarising our project learning into the areas of collaborative robotics, remote operation and unforeseen benefits.
Lessons Learned from uHTS Assay Technologies in the European Screening Centre at European Lead Factory
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Open to view video.
The European Lead Factory has given European academics/SMEs access to ~0.5 million unique compounds and state-of-the-art ultra-high-throughput (uHTS) platform with the aim to deliver innovative drug discovery starting points. From 2013-2018, 154 proposals for 6 target classes across 8 therapeutic areas were submitted, 88 of which were accepted by the selection committee. During this period, 76 primary assays based on 8 different measurement technologies were optimized and miniaturized to 1536-well plate format; 72 uHTS campaigns were carried out and 60 follow-up activities using orthogonal, deselection, selectivity and biophysical assay technologies were finalized. This ambitious program showed that besides the quality of the library, the success of any HTS campaign is largely dependent on the frameworks and techniques used in assay development as well as hit triaging phase, particularly due to undesired compound-assay interference. To dissect such liabilities early in assay development phase, we have implemented the “robustness set” collection; comprising of various assay-interfering and ‘clean’ compound classes providing a framework to tailor assay conditions prior to screening and foresee assay technologies needed to triage the false-positive hits.