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Cancer Drug Design and Discovery
 
 

Cancer Drug Design and Discovery, 2nd Edition

 
Cancer Drug Design and Discovery, 2nd Edition,Stephen Neidle,ISBN9780123965219
 
 
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S Neidle   

Academic Press

9780123965219

9780123972286

640

235 X 191

The second edition of this authoritative reference features the latest on the design and development of new anticancer small molecules, including topics such as the identification of molecular targets, cancer genomics, personalized medicine and more.

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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

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.

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.

Stephen Neidle

Stephen Neidle, DSc, PhD, ARCS, FRSC, Director of Cancer Research UK Biomolecular Structure Group, Director of the Centre for Cancer Medicines, Professor of Chemical Biology, The School of Pharmacy, University College London, UK

Affiliations and Expertise

The School of Pharmacy, University College London, UK

View additional works by Stephen Neidle

Cancer Drug Design and Discovery, 2nd Edition

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

Quotes and reviews

"…offers unique information on the discovery and design of new anticancer agents, covering recent notable successes resulting from the human genome and cancer genomics projects…an excellent reference for translational researchers interested in cancer biology and medicine as well as students in pharmacy, pharmacology, or medicinal and biological chemistry…"--Anticancer Research 34, 2014
"The second edition of this book walks readers through the myriad cancer drugs and their molecular targets, with a special emphasis on past, present, and future drug design efforts... the book examines both drugs currently in the clinic and those merely on the drawing board…This comprehensive update of the 2008 edition will serve student or experienced cancer researchers well as a reference on anticancer drug development." Rating: 4 Stars--Doody.com, March 21, 2014
"Specialists in cancer and pharmaceuticals, most in academic settings, look at basic principles of cancer drugs, methodology, drugs in the clinic, new agents, and the reality of cancer drugs in the clinic…They do include many case studies, and some chapters provide questions for classroom use."--ProtoView.com, February 2014

 
 
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