Contents:

Accelerating Lead Generation: Emerging technologies and strategies Executive Summary Introduction 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 Introduction 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 Summary Introduction 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 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 Conclusions Chapter 3 Innovations in biological assay development Summary Introduction 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 Conclusions Chapter 4 ADME and toxicology in lead generation Summary Introduction 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 Chemoinformatic methods Toxicogenomics High content screening Zebrafish Whole animal imaging Determining mutagenic and clastogenic potential Measuring HERG liability Investigating CYP inhibition and induction Conclusions Chapter 5 Lead generation strategies in the pharma industry Summary Introduction Lead generation teams Case studies Bayer Boehringer Ingelheim Millennium Pharmaceuticals (Takeda) Conclusions Chapter 6 R&D models, innovation & future success of lead generation Summary Introduction 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 (1999-2008) Figure 1.2: Patent losses occurring between 2008-2014 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 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

Companies Mentioned

- Bayer - Boehringer Ingelheim - Millennium Pharmaceuticals (Takeda)