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Fragment-Based Drug Discovery: Technologies, Applications, and Pipelines

Comparison of development candidates derived from fragment-based screens has suggested that such an approach can provide compounds with more drug-like properties than those derived from more conventional screening efforts. The development and application of fragment-based screening methodologies form the focus of this report, which discusses:

  • The rationale for using fragments, considering the advantages from their position in chemical space and as leads for targets that have proved intractable to other methods
  • The various methods that have been described for use in fragment-based screens, highlighting the advantages and disadvantages of the more widely used approaches
  • Case histories that illustrate the success of fragment-based drug design in identifying novel, tractable leads that can be progressed to development candidates
  • Diverse specialist companies that exploit fragment-based screening or that offer services to other organizations that exploit specific aspects of fragment-screening technologies
  • How these developments will impact the future of pharmaceutical R&D with respect to small-molecule therapeutics
  • Findings and analysis from an Insight Pharma Reports survey that was conducted on fragment-based screening

The screening of low-molecular weight chemicals (fragments) has emerged as a rational, increasingly popular approach for the identification of novel, chemically tractable leads for the development of new therapeutic agents. This Insight Pharma Report, Fragment-Based Drug Discovery: Technologies, Applications, and Pipelines, examines the many issues that must be considered vis-a-vis employment of fragment-based screening approaches. Chemical considerations are examined, including the impact of high-throughput screening (HTS) and its attendant shortcomings, the concept of chemical space, and factors that must be considered when assessing fragment candidates for inclusion in screening libraries. The criteria for selecting possible fragments (Rule of 3), and for assessing contributions to binding (e.g. ligand efficiency), are discussed. The increasing number of different assay protocols that have proven useful in fragment screening are reviewed; these various methods are considered in the context of their specific advantages and limitations.

This Insight Pharma Report presents several case studies illustrating the success of fragment-based drug design in identifying novel, tractable leads that can be progressed to development candidates. Each of these examples highlights the application of different biophysical methods to a specific class of targets. The increasing popularity of fragment-based screening methods is highlighted by the ever-expanding number of companies that provide fragment-based screening services. We briefly review selected specialist companies, comprising those which have specialized in using fragment-based design to identify their own lead compounds, those which offer specialized fragment-based screening services, and those which provide fragment libraries.

Almost all major pharmaceutical companies have now adopted fragment-based screening programs for at least some of their discovery efforts, while many smaller companies have found the method invaluable for lead identification. This has led to around 30 fragment-derived leads having progressed to clinical development, and one such drug having already gained approval (ZELBORAF [vemurafenib]). Fragment-Based Drug Discovery: Technologies, Applications, and Pipelines concludes with an examination of corporate interest in fragment screening, together with a review of compounds in clinical development that are derived from leads identified in fragment-screening programs. Finally, results from Insight Pharma Reports' “Fragment-Based Screening” survey are presented and analyzed.

About the Author

Peter Norman, MBA, PhD, is a pharmaceutical consultant and analyst based in Burnham Beeches, near Windsor, England, with specialist knowledge of the respiratory disease and inflammation markets. He has written and presented widely on various aspects of respiratory disease, generics, orphan drugs and developments in therapeutic markets. Dr. Norman has over 20 years' experience of the pharmaceutical industry in both R&D and competitive intelligence. His publications incl ude many reviews and management reports, sixteen original scientific papers and eleven patents. Dr. Norman holds science degrees from Cambridge University and Brunel University plus an MBA degree from the Open University.

Table of Contents

Executive Summary

Chapter - 1

INTRODUCTION

  • 1.1. Overview
  • 1.2. Declining Innovation
  • 1.3. Difficult Targets

Chapter - 2

CHEMICAL CONSIDERATIONS

  • 2.1. Introduction
  • 2.2. The Impact of HTSChemical Libraries
    • The Rule of 5 (Lipinski)
    • Molecular Obesity
  • 2.3. Chemical SpaceDrug Space
  • 2.4. FragmentsFragments as Leads
    • What Are Suitable Fragments?
    • Rule of 3
    • Ligand Efficiency and Lipophilic Ligand Efficiency
  • 2.5. Fragment LibrariesCharacteristics
    • Size

Chapter - 3

SCREENING APPROACHES

  • 3.1. Introduction
  • 3.2. In Silico Methods
  • 3.3. Surface Plasmon Resonance Methods
  • 3.4. NMR ScreeningSolution Phase
    • Solid Phase
  • 3.5. X-Ray Methods
  • 3.6. Mass Spectral Methods
  • 3.7. Isothermal Calorimetry
  • 3.8. Capillary Electrophoresis
  • 3.9. Microfluidic Assays
  • 3.10. Other Approaches
  • 3.11. Bioassays
  • 3.12. Overview

Chapter - 4

CASE HISTORIES

  • 4.1. Introduction
  • 4.2. Abbott's Bcl Inhibitors
  • 4.3. Astex' Kinase Inhibitors
  • 4.4. Heptares' Adenosine A2a Antagonists
  • 4.5. Vernalis' Hsp90 Inhibitors
  • 4.6. Vemurafenib
  • 4.7. Conclusions

Chapter - 5

SPECIALIST COMPANIES

  • 5.1. Introduction
  • 5.2. Alveus Pharmaceuticals
  • 5.3. Astex Pharmaceuticals
  • 5.4. Beactica
  • 5.5. BioFocus
  • 5.6. BioLeap
  • 5.7. CRELUX
  • 5.8. Crown Biosciences
  • 5.9. Emerald BioStructures
  • 5.10. Evotec
  • 5.11. Graffinity
  • 5.12. Heptares
  • 5.13. Iota Pharmaceuticals
  • 5.14. Kinetic Discovery
  • 5.15. NovAliX
  • 5.16. Nuevolution
  • 5.17. Polyphor
  • 5.18. Proteros Fragments
  • 5.19. Pyxis Discovery
  • 5.20. Selcia
  • 5.21. Silicos
  • 5.22. Sprint Bioscience
  • 5.23. Structure Based Design
  • 5.24. Sygnature Discovery
  • 5.25. Vernalis
  • 5.26. Viva Biotech
  • 5.27. Zenobia Therapeutics
  • 5.28. ZoBio

Chapter - 6

OUTLOOK

  • 6.1. Introduction
  • 6.2. New Methods
  • 6.3. Corporate InterestMajor Companies
    • Other Companies
  • 6.4. Development Compounds
  • 6.5. Conclusion

Chapter - 7

RESULTS FROM INSIGHT PHARMA REPORTS' FRAGMENT-BASED SCREENING SURVEY

  • 7.1. Survey Description
  • 7.2. Survey Analysis
  • 7.3. Survey Results

References

Glossary

Company Index

FIGURES

  • Figure 1.1. NDA and BLA Approvals, 2000 - 2011
  • Figure 1.2. The Druggable Genome: a) Exploited, b) Potential
  • Figure 2.1. Schematic Representation of Chemical Space
  • Figure 2.2. Progression to Candidates from Leads
  • Figure 2.3. Progression to Candidates from Fragment Leads
  • Figure 2.4. The Recognition of Some Fragments by a Target Showing a) Unbound and b) Bound Fragments
  • Figure 2.5. Probability of Binding Ligands of Increasing Complexity
  • Figure 3.1. Usable Concentration Ranges of Different Assays
  • Figure 3.2. Schematic Comparison of the Throughput of and Information Content from Key Fragment-Screening Methods
  • Figure 4.1. Progression from Fragment Hits to ABT-737
  • Figure 4.2. Fragments to Candidates as Described by Astex
  • Figure 4.3. Comparison of Merck's Development Compound with Heptares' Fragment-Derived Lead
  • Figure 4.4. Vernalis' Progression from a Fragment Hit to a Development Candidate
  • Figure 4.5. Vernalis' Progression From Another Fragment Hit to a Second Development Candidate
  • Figure 4.6. Plexxikon's Progression from a Fragment Hit to the Marketed Drug Vemurafenib
  • Figure 7.1. Size of Fragment Libraries Employed by Survey Respondents

SURVEY EXHIBITS

  • Question 1. What is your organization type?
  • Question 2. Is your organization currently running any fragment-based screens?
  • Question 3. If your organization is not currently running any fragment-based screens, has it previously run any?
  • Question 4. What is the size of the fragment library employed (actual [not in silico])?
  • Question 5. How many assays has this library been used in?
  • Question 6. In what proportion of assays have useful hits been identified?
  • Question 7. Have hits led to 1) novel chemotypes, 2) success for previously intractable targets, 3) lower-molecular weight leads than conventional screening?
  • Question 8. Which physical screening methods have you used to evaluate fragments to identify leads?
  • Question 9. Have you had success with more than one screening method?
  • Question 10. Have you used more than one (fragment screening) approach for the same target?
  • Question 11. If you have used more than one (fragment screening) approach for the same target, have similar hits been achieved from both approaches?
  • Question 12. If in silico methods have been explored, were useful results obtained?
  • Question 13. Do you consider/prefer screening methods that provide some information on the nature of the structural interaction (i.e., X-ray and/or NMR) over methods that don't provide such data?
  • Question 14. Do you believe fragment screening is best effected by using internal resources, external resources, or a mix of both?
  • Question 15. Does the nature of the target affect the choice of where to run the fragment screen?
  • Question 16. Do you envisage continued growth in the use of fragment-based screens?

TABLES

  • Table 5.1. Selected Companies Specializing in Aspects of Fragment-Based Discovery
  • Table 6.1. Development Compounds Derived from Fragment Screens
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