Accelerating Lead Generation: Emerging technologies and strategies

Table of Contents

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
• 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