Cancer Drug Design and Discovery

Cancer Drug Design and Discovery

2nd Edition - September 30, 2013

Write a review

  • Editor: Stephen Neidle
  • eBook ISBN: 9780123972286
  • Hardcover ISBN: 9780123965219

Purchase options

Purchase options
DRM-free (EPub, PDF, Mobi)
Available
Sales tax will be calculated at check-out

Institutional Subscription

Free Global Shipping
No minimum order

Description

Cancer Drug Design and Discovery, Second Edition is an important reference on the underlying principles for the design and subsequent development of new anticancer small molecule agents. New chapters have been added to this edition on areas of particular interest and therapeutic promise, including cancer genomics and personalized medicine, DNA-targeted agents and more. This book includes several sections on the basic and applied science of cancer drug discovery and features those drugs that are now approved for human use and are in the marketplace, as well as those that are still under development. By highlighting some of the general principles involved in taking molecules through basic science to clinical development, this book offers a complete and authoritative reference on the design and discovery of anticancer drugs for translational scientists and clinicians involved in cancer research.

Key Features

  • Provides a clinical perspective on the development of new molecularly targeted anticancer agents with the latest and most promising chemotherapeutic approaches
  • Offers a broad view of where the field is going, what tools drug discovery is using to produce new agents and how they are evaluated in the laboratory and clinic
  • Features 6 new chapters devoted to advances in technology and successful anticancer therapies, such as cancer genomics and personalized medicine, DNA-targeted agents, B-Raf inhibitors and more
  • Each chapter includes extensive references to the primary and review literature, as well as to relevant web-based sources

Readership

Translational researchers and clinicians interested in modern drug discovery, cancer biology and medicine, as well as graduate and undergraduate students in pharmacy, pharmacology or medicinal and biological chemistry.

Table of Contents

  • Introduction

    Cancer Drug Design and Discovery

    Foreword

    Editor Biography

    Contributors

    Part I: Basic Principles and Methodology

    Chapter 1. Modern Cancer Drug Discovery: Integrating Targets, Technologies, and Treatments for Personalized Medicine

    Abstract

    Acknowledgments

    Introduction: Changing Times

    Successes and Limitations

    Integrated Small-Molecule Drug Discovery and Development

    New Molecular Targets: The Druggable Cancer Genome and Epigenome

    From Drug Target to Development Candidate

    Examples of Case Histories for Molecularly Targeted Cancer Therapeutics

    Biomarkers, the Pharmacological Audit Trail, and Clinical Development

    Conclusions and Outlook: Toward Individualized Molecular Cancer Medicine

    Disclosure

    References

    Recommended further reading

    Useful Websites

    Chapter 2. Pharmacogenomics and Personalized Medicines in Cancer Treatment

    Abstract

    Introduction

    Molecular Genetic Basis for Variation in Drug Response

    Methodologies for Pharmacogenomic Discovery, Validation, and Implementation

    Clinically Important Pharmacogenomic Markers for Treatment Response

    Conclusions

    References

    Chapter 3. Natural Product Chemistry and Cancer Drug Discovery

    Abstract

    Acknowledgments

    Introduction

    Exemestane (Aromasin)

    Fulvestrant (Faslodex)

    Flavonoids

    Bexarotene (Targretin)

    Epothilones

    Maytansine

    Geldanamycin

    UCN-01

    Camptothecin

    Prodigiosin

    Azacitidine

    FK-228

    Hemiasterlin

    Halichondrin

    Trabectedin

    Conclusions

    References

    Chapter 4. Structural Biology and Anticancer Drug Design

    Abstract

    Introduction

    Structural Biology Methods

    Structural Biology and Structure-Based Drug Design

    Fragment Screening Using X-ray Crystallography

    Case History—Protein Kinase B Inhibitors from Fragment Hit to Clinical Candidate

    Conclusions

    References

    Part II: Drugs in the Laboratory and Clinic

    Chapter 5. Temozolomide: From Cytotoxic to Molecularly Targeted Agent

    Abstract

    Acknowledgments

    Introduction

    Toward Imidazotetrazines and Azolastone (Mitozolomide)

    From Mitozolomide to Temozolomide

    Synthesis and Chemistry of Temozolomide

    Early Clinical Trials on Temozolomide

    Mode of Action of Temozolomide

    Epigenetic Silencing of the MGMT Gene

    New Analogs of Temozolomide

    Summary: Temozolomide, Targets, Molecular Targets, and Validated Targets

    References

    Chapter 6. Temozolomide: Patents and the Perils of Invention

    Abstract

    Acknowledgments

    Introduction

    History of US Patent 5,260,291 (1993)

    Cancer Research Technology Ltd et al. (Plaintiffs) vs Barr Laboratories Inc. et al. (Defendants)

    The Verdict

    The Appeal(s)

    Conclusions

    References

    Chapter 7. A New Generation of Cell-Targeted Drugs for Cancer Treatment

    Abstract

    Acknowledgments

    Introduction

    Vintafolide (MK-8109 or EC145): A Novel Folate-Targeted Vinca Alkaloid

    F14512: A Spermine-Conjugated Epipodophyllotoxin

    Conclusions

    References

    Chapter 8. Inhibition of DNA Repair as a Therapeutic Target

    Abstract

    Acknowledgments

    Introduction

    O6-Alkylguanine DNA Alkyltransferase

    Base Excision Repair and Single-Strand Break Repair

    Mismatch Repair (MMR)

    Double-Strand Break Repair: Nonhomologous End Joining

    Double-Stand Break Repair: Homologous Recombination Repair

    Exploiting Synthetic Lethality for Cancer Treatments

    Summary and Conclusions

    Problem Set

    References

    Recommended Further Reading

    Useful Websites

    Chapter 9. Exploiting Cancer Dependence on Molecular Chaperones: HSP90 Inhibitors Past, Present, and Future

    Abstract

    Introduction

    Biology of HSP90

    HSP90 in Cancer

    Discovery and Development of HSP90 Inhibitors: From Chemical Probes to Drugs

    Agents that Bind to the N-Terminal HSP90 ATP-Binding Pocket

    Agents that Bind to Other Sites on HSP90

    Potential Future Targets

    Summary and Future Directions

    Conflict of Interest

    References

    Chapter 10. Inhibitors of Tumor Angiogenesis

    Abstract

    Acknowledgments

    Introduction: the Tumor Angiogenic Process

    The Complexity of “Angio-network” Signaling

    Antiangiogenic Strategies

    Resistance: The Antiangiogenic Therapy Loop

    Clinical and Biological Markers for Antiangiogenic Strategies

    Conclusions

    References

    Chapter 11. The Renaissance of CYP17 Inhibitors for the Treatment of Prostate Cancer

    Abstract

    Prostate Cancer: Epidemiology, Diagnosis, and Current Therapies

    Androgens and Hormone Therapy

    Inhibition of CYP17 as a Promising Treatment for Prostate Cancer

    Steroidal CYP17 Inhibitors

    Nonsteroidal CYP17 Inhibitors

    CYP17 Inhibitors in the Post-abiraterone Era

    Renaissance: Summary and Conclusions

    References

    Chapter 12. Apoptosis in Cancer: Mechanisms, Deregulation, and Therapeutic Targeting

    Abstract

    Acknowledgments

    Introduction

    Mechanisms of Apoptosis

    Defects in Apoptosis and Antitumor Drug Resistance

    Therapeutic Targeting of Apoptosis

    Conclusion

    References

    Chapter 13. Targeting the MDM2–p53 Protein–Protein Interaction: Design, Discovery, and Development of Novel Anticancer Agents

    Abstract

    Acknowledgments

    Introduction

    p53 and Cancer

    Targeting the MDM2–p53 Interaction

    MDM2–p53 Inhibitors

    MDMX–p53 Inhibitors

    Clinical Status of MDM2–p53 Inhibitors

    Conclusions

    References

    Chapter 14. Targeting Altered Metabolism—Emerging Cancer Therapeutic Strategies

    Abstract

    Metabolic Alterations in Cancer

    Regulation of Oxidative Stress Homeostasis in Cancer

    Development of Therapeutics Targeting Cancer Metabolism

    Perspective

    References

    Chapter 15. Inhibitors of the Phosphatidylinositol 3-Kinase Pathway

    Abstract

    Introduction

    Mechanism of Inhibition

    Evolution of the Major Classes of PI3K Inhibitors

    Pan-Inhibitors of PI3K and mTOR

    Selective Inhibitors of PI3K

    Irreversible PI3K Inhibitors (Fig. 15.13)

    Summary and Conclusions

    References

    Chapter 16. Antibody–Drug Conjugates Delivering DNA Cytotoxics

    Abstract

    Introduction

    Composition of Antibody–Drug Conjugates

    Antibody–Drug Conjugates Containing Conventional DNA-Interacting Agents

    Antibody–Drug Conjugates Containing DNA-Cleaving Agents

    Antibody–Drug Conjugates Containing DNA Minor Groove–Alkylating and Cross-Linking Agents

    Future Development of Antibody–Drug Conjugates

    References

    Chapter 17. Inhibition of Telomerase: Promise, Progress, and Potential Pitfalls

    Abstract

    Introduction

    Potential Caveats of Telomerase Inhibitors

    Direct Enzymatic Inhibition of Telomerase by Small-molecule Drugs

    Indirect Telomerase Inhibition with G-quadruplex-stabilizing Molecules

    Conclusions and Future Prospects

    References

    Chapter 18. Targeting B-RAF: The Discovery and Development of B-RAF Inhibitors

    Abstract

    Acknowledgments

    B-RAF Kinase Signaling

    Regulation and Structure of B-RAF

    Sorafenib (Nexavar®, or BAY43-9006)

    RAF265

    LGX818

    Vemurafenib (Zelboraf®, or PLX4032)

    Dabrafenib (TAFINLAR® or GSK2118436)

    XL281 (BMS-908662)

    Resistance Mechanisms

    Combinatorial Therapies

    Conclusions

    References

    Part III: The Reality of Cancer Drugs in the Clinic

    Chapter 19. Failure Modes in Anticancer Drug Discovery and Development

    Abstract

    Introduction

    Problems in Clinical Development

    Phase I

    Phase II

    Phase III

    Conclusions

    References

    Chapter 20. Anticancer Drug Registration and Regulation: Current Challenges and Possible Solutions

    Abstract

    Introduction

    The Regulatory Framework in the United States

    The Regulatory Framework in the European Union

    Current Issues and Future Directions in Anticancer Drug Regulation

    Conclusions

    References

    Color Plates

    Glossary

    Index

Product details

  • No. of pages: 640
  • Language: English
  • Copyright: © Academic Press 2013
  • Published: September 30, 2013
  • Imprint: Academic Press
  • eBook ISBN: 9780123972286
  • Hardcover ISBN: 9780123965219

About the Editor

Stephen Neidle

Stephen Neidle
Stephen Neidle is an Emeritus Professor of Chemical Biology at University College London, where he has also been the Director of Research in the School of Pharmacy. He has published over 500 primary papers and reviews and is a principal inventor on 14 patent filings. He has also written and edited several books on nucleic acids and anti-cancer drugs.

Affiliations and Expertise

Emeritus Professor of Chemical Biology, The School of Pharmacy, University College London, UK

Ratings and Reviews

Write a review

There are currently no reviews for "Cancer Drug Design and Discovery"