Lead Optimization Strategies: Future developments, threats and opportunities for big pharma, specialty pharma and biotech

Table of Contents

Executive Summary

• The importance of lead optimization
• Traditional big pharma strategies
• Alternative strategies used by specialty pharma and biotech
• Future developments in lead optimization
• Commercial threats and opportunities

Chapter 1 The importance of lead optimization

• Summary
• Introduction
• Current issues facing the pharmaceutical industry
• Introduction to lead optimization
  • Hit generation
  • Lead identification
  • Lead optimization
  • Lead optimization in the R&D process
  • Time and costs associated with lead optimization
• Commercial and clinical importance of lead optimization
• Lead optimization strategies
  • Traditional big pharma strategies
  • Alternative strategies used by specialty pharma and biotech
  • Differences in strategy

Chapter 2 Traditional big pharma strategies

• Summary
• Introduction
• A typical screening cascade
• Key strategic components in lead optimization
  • Team organization for lead optimization
    • Medicinal chemistry functionality
  • Sources of hits and leads
    • Proprietary collections
    • Commercial non-exclusive libraries
    • Natural products
    • Academic groups
    • Advantages and disadvantages of hit sources
  • Improving the quality of compound collections
    • Case study 1: AstraZeneca
    • Case study 2: GSK
  • Setting the criteria for hits, leads and candidate drugs
• Key technologies involved in lead optimization
  • HTS technologies
  • NMR
  • Utility of modeling in lead optimization
    • In silico modeling
    • In vitro modeling
  • Computational chemistry
    • Virtual screening
    • Library design
  • HT protein crystallography
  • Application of molecular biology in lead optimization
  • ADMET screening
    • The role of DMPK in lead optimization
    • Metabolism and covalent binding
    • Toxicity
    • Assays for assessing toxicity
  • HT chemistry
    • Preparative LC-MS chromatography
    • Supercritical Fluid Chromatography (SFC)
• Outsourcing lead optimization
• Weaknesses of the traditional lead optimization model
  • Sequential data gathering
  • Single compound synthesis
  • Animal models
• Conclusions

Chapter 3 Alternative strategies used by specialty pharma & biotech

• Summary
• Introduction
• Alternative lead optimization strategies
• Mimicking big pharma cascades
  • Polypharmacology
• Short/partial screening cascades
  • Case Study: ArQule
• Computational approaches
  • Case study: Locus Pharmaceuticals
• Alternative approaches to screening
• HT crystallography
• Nanotechnology
  • Scanning probe microscopy
  • Nanoparticle formulation
• Outsourcing lead optimization
• Lessons from specialty pharma/biotech strategies
• Conclusions

Chapter 4 Future developments in lead optimization

• Summary
• Introduction
• Key improvement opportunities
• Reductions in time
  • In silico models
• Producing fewer compounds of higher quality more efficiently
  • Cheminformatics
• Bridging the chemistry and target space gap
• Miniaturization of chemistry
• More efficient screening cascades
  • Systems biology
  • Zebrafish model
• Reducing high attrition rates during lead optimization
  • The 'omic revolution: transforming drug discovery
  • Technology developments
• Lead optimization, 2010-2015
• Conclusions

Chapter 5 Commercial threats and opportunities

• Summary
• Introduction
  • Threats
  • Opportunities
• Commercial threats
  • Industry consolidation
  • Increased drug safety requirements
  • Avoidance of untested innovative new technologies
  • Drive towards lower risk "me too" drugs
• Commercial opportunities
  • The genomic revolution
  • Changes to orphan drug legislation
  • Changes in regulatory guidelines: Biomarkers helping to improve the chance
  • of new drug approvals
  • Combinatorial biomarkers aiding efficiency within the D&D process
  • In- and out-Licensing opportunities to create new revenues streams for all
  • players within the industry
• Conclusions

Chapter 6 Appendix

• Abbreviations
• References
• Index