Accelerating Lead Generation: Emerging Technologies and Strategies

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1 Brochure More information from Accelerating Lead Generation: Emerging Technologies and Strategies Description: The number of approvals for new drugs and biologics has fallen steadily in recent years, despite increasing R&D expenditure. Cost effective and innovative approaches to drug discovery and development have therefore become particularly important to ensure shareholder value. Improvements to the lead generation process are a key initiative for company s aiming to avoid expensive compound failures in the latter stages of the drug discovery process. Accelerating Lead Generation: Emerging technologies and strategies is a report that provides an in-depth examination of state-of-the-art technologies for lead generation. This report assesses the potential of new and emerging technologies for improving the quality of drug candidates entering clinical research, and reviews the benefits associated with different approaches to lead generation, including high throughput screening, fragment based drug discovery and virtual screening. The lead generation strategies adopted by leading pharma companies are evaluated to provide strategic recommendations for success, and the trends that are shaping the future acceleration of lead generation are identified. Key Findings Truly novel molecules are far more likely to be identified during the optimization process through the manipulation of structures than through screening. Methods include forming a new ring structure within a compound (or opening one out), the replacement of functional groups with bioisosteres and scaffoldhopping. Emerging methods for scaffold hopping based on force fields are growing in popularity. Virtual screening and fragment-based drug discovery will complement HTS-generated data rather than replacing it. The low cost of virtual screening and its potential for improving library design means that large screens can be carried out in the earliest stages of drug discovery. Conversely, it is best to apply fragmentbased drug discovery to targets for which quality structural information is readily available. New technologies that replace fluorescence-based or radioligand displacement assays are growing in throughput and are being rapidly introduced across the industry. Innovations that improve the throughput and sensitivity of label-free technologies are either introducing them to drug discovery as secondary assays, or promoting secondary assay technologies to primary versions. Improved methods for handling data, multiplexing assays, and using primary cells, 3D cell culture or stem cell derived populations will increase the physiological relevance of data collected. Novel in vivo models, such as zebrafish and whole animal imaging may also provide additional data. Use this report to... - Analyse the potential of emerging technologies for improving the quality of drug candidates and understand how such innovations can improve the ability of fragment based drug discovery and virtual screening to identify new lead compounds. - Explore recent developments in high throughput screening with this report s analysis of innovations in biological assay development, including improvements in vitro assays, cell-based assay technology and invivo methods for lead generation. - Examine the role of ADME and toxicology in accelerating lead generation with this report s analysis of innovations in the assessment of ADME characteristics and toxicology at the lead generation stage. - Evaluate the lead generation strategies of major companies with this report s case study analysis of Bayer, Boehringer Ingelheim, Millennium Pharmaceuticals (Takeda), and understand the importance of R&D models, academia collaborations and technological innovations to lead generation success. Explore issues including... The need for innovation. In response to declining R&D productivity, companies are aiming to address the areas that are most likely to lead to the failure of a new compound. The overall likelihood of a project

2 progressing from Phase 1 to approval is roughly 20%, although in some therapeutic areas this may be as low as 8%. Failure in the late stages of drug development remains a real problem for the industry. Emerging assay technologies. Novel assays are required to improve the output of HTS (high throughput screening). Key areas of innovation include the development of label-free assay technologies and the increasing use of cell-based assays/high content assays. The early identification of ADME and toxicology issues. Primary HTS focuses on compound potency rather than any of the other numerous attributes required for a drug to succeed in the clinic. These include cell permeability, solubility, plasma protein binding, pharmacokinetics, bioavailability and predicted metabolism, as well as target specificity and toxicology. Discover... - What has driven interest in the improvement of lead generation in recent years? - Which are the key technologies in the drive to improve lead generation and identify the most suitable lead series for further optimization? - What are the most promising areas of innovation in lead generation? - What strategies are the leading pharma companies adopting in order to measure key endpoints for lead generation in a high throughput, parallel and cost effective fashion? - How can companies take a truly novel approach to lead generation through the use of innovative new technology? Contents: Accelerating Lead Generation: Emerging technologies and strategies Executive Identifying hits: library design, virtual screening and fragment based drug discovery Innovations in biological assay development ADME and toxicology in lead generation Lead generation strategies in the pharma industry R&D models, innovation and future success of lead generation Chapter 1 The drug discovery process: defining lead generation Hit finding and verification Hit optimization Lead optimization Criteria for potential lead compounds Chemistry Pharmacology Absorption, Metabolism, Excretion, Distribution (ADME) and Toxicity Chapter 2 Identifying hits: library design, virtual screening and fragment based drug discovery Hit to lead identifying possible structures Compound selection Physiochemical properties Chemical optimization and modification of hits Engineering novelty Beyond HTS alternative methods for identifying hits Fragment-based drug discovery Companies involved in FBDD Case study: decode chemistry & biostructures Inc Case study: Zenobia Therapeutics Can FBDD generate successful new drugs? Technology improvements driving FBDD

3 Improving x-ray crystallography Improvements in NMR spectroscopy for FBDD High concentration biological assays Improving biophysical methods Improving fragment library design Chemistry-based methods HTS vs FBDD Virtual screening Target based virtual screening Case study: Epix Pharmaceuticals When to use virtual screening Target based virtual screening: challenges Ligand based screening Commercial virtual screening platforms Chapter 3 Innovations in biological assay development Improving high throughput screening Identifying valid hits A quantitative approach to primary screening Compound management and quality assessment Dispensing Informatics and data analysis Improving in vitro assays for HTS Surface plasmon resonance Isothermal titration calorimetry and nanocalorimetry Back-Scattering Interferometry Differential scanning fluorimetry High throughput Mass Spectrometry Bio-layer interferometry Innovations in cell-based assay technology Automated confocal microscopy methods Flow cytometry Laser scanning cytometry Label-free cell-based screens Photonic crystal biosensors Dynamic mass redistribution Impedance-based whole cell biosensors Other cell-based assays Reverse arrays Enzyme Fragment Complementation HCS and SAR Novel cell types and cultures In vivo methods in lead generation Zebrafish Whole animal imaging and microscopy Chapter 4 ADME and toxicology in lead generation Assessing ADME characteristics Oral absorption P-Glycoprotein interactions Plasma protein binding Clearance Metabolic stability Selectivity and off-target effects Solubility Toxicology at the lead generation stage In silico structure-toxicity relationships

4 Chemoinformatic methods Toxicogenomics High content screening Zebrafish Whole animal imaging Determining mutagenic and clastogenic potential Measuring HERG liability Investigating CYP inhibition and induction Chapter 5 Lead generation strategies in the pharma industry Lead generation teams Case studies Bayer Boehringer Ingelheim Millennium Pharmaceuticals (Takeda) Chapter 6 R&D models, innovation & future success of lead generation R&D models: influence on lead generation R&D models Outsourcing and offshoring Dealing with academia Pharma collaboration Co-opetition Innovation and the future Targets and HTS Focus on RNA Focus on lead optimization Nanochemistry returning chemistry to its central role in drug discovery Lead generation now and in the future Chapter 7 Appendix Primary research methodology Acknowledgments Glossary Index Bibliography List of Figures Figure 1.1: Pharma industry productivity decline ( ) Figure 1.2: Patent losses occurring between Figure 1.3: The drug discovery process Figure 1.4: Example of a lead generation workflow Figure 1.5: Technologies involved in lead generation Figure 2.6: Use of structural information in structure-based drug design Figure 2.7: Examples of the chemical structures of compounds discovered using FBDD Figure 2.8: ZoBio s target immobilized NMR spectroscopy method for fragment-based drug discovery Figure 3.9: Areas of innovation in high throughput screening Figure 3.10: Acoustic droplet ejection Figure 3.11: Attributes required of software for HTS data storage and analysis Figure 3.12: Kinetic characterization of 5 lead series using SPR (Biacore) Figure 3.13: Bio-Layer Interferometry from ForteBio Figure 3.14: Advantages of cell-based screening in HTS Figure 3.15: Principle of detection: cell based assays with the Epic system from Corning Figure 3.16 Principle of the EFC assay for a biochemical target: HitHunter from DiscoveRx Figure 4.17: ADME and toxicology data available in high throughput assays Figure 4.18: The Safety Intelligence Program from BioWisdom

5 Figure 4.19: Examples of assertions in the Safety Intelligence Program from BioWisdom Figure 4.20: A typical toxicogenomics workflow in the pharma industry Figure 5.21: Key innovations in lead generation technologies Figure 5.22: Key activities of medicinal chemists during lead generation Figure 5.23: ADME-Tox traffic light criteria in use at Bayer Figure 5.24: Discovery-Assays-By-Stage paradigm of Millennium Pharmaceuticals Figure 6.25: The microreactor-based lead discovery system List of Tables Table 2.1: Fragment-based drug discovery: the pros and cons Table 2.2 Techniques used to assess fragment binding for FBDD Table 2.3: Examples of companies with product pipelines derived from FBDD Table 2.4: Examples of compounds discovered using FBDD Table 2.5: Rule of Three criteria for a fragment library Table 2.6: Examples of companies offering fragment libraries and collections for FBDD Table 2.7: Examples of companies offering software for virtual screening Table 3.8: Examples of companies providing software for HTS information storage and analysis 71 Table 3.9: Emerging technologies for high throughput screening Table 3.10: A comparison of free-solution, label-free molecular interaction techniques Table 3.11: Examples of recent collaborations between stem cell companies and big pharma for the use of stem cells in drug discovery research Table 3.12: Advantages and disadvantages of zebrafish for compound screening Table 3.13: Companies offering zebrafish screening products and services Table 3.14: Advantages of molecular imaging of whole animals for preclinical studies Table 3.15: Half lives of important positron emitting isotopes Table 4.16: Examples of contract laboratories offering HCA cytotoxicity screening Table 4.17: Examples of higher throughput or miniaturized versions of the Ames test Table 6.18: Recent examples of academic drug discovery funding by big pharma Ordering: Order Online - Order by Fax - using the form below Order by Post - print the order form below and send to Research and Markets, Guinness Centre, Taylors Lane, Dublin 8, Ireland.

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