Cancer (eBook)

Volume Editor 5
Editorial Board 5
Topics in Medicinal Chemistry Also Available Electronically 6
Preface to the Series 7
Preface to Volume 1 8
Contents 10
Overview 12
1 Introduction 13
2 Historical Perspective 13
3 Cytotoxic Drugs 14
4 Anti-hormonal Drugs 16
5 Targeted Drugs 17
6 Structure of This Volume 23
7 Conclusion 25
References 25
Anti-hormone Therapy: Principles of EndocrineTherapy of Cancer 30
1 Introduction 32
2 Chemistry and Pharmacology of Endocrine Therapy 45
3 Conclusion and Outlook 84
References 85
Inhibition of Growth Factor Signaling by Small- Molecule Inhibitors of ErbB, Raf, and MEK 94
1 Introduction 96
2 Biological Background and Rationale 96
3 Structural Biology 99
4 Inhibitors of the ErbB Family 106
5 Inhibitors of Raf 124
6 Inhibitors of MEK 128
7 Biomarkers 132
8 Conclusions and Outlook 135
References 137
Farnesyl Protein Transferase Inhibitors: Medicinal Chemistry, MolecularMechanisms, and Progress in the Clinic 144
1 Introduction and Historical Overview 146
2 Biochemistry of Farnesyl Protein Transferase 147
3 Downstream Effectors 149
4 Biomarkers 157
5 Farnesyl Transferase Inhibitors 158
6 Clinical Experience 168
7 Further Developments 168
8 Conclusion and Perspectives 170
References 171
Survival Signaling 180
1 Introduction 182
2 Insulin-like Growth Factor I Receptor 183
3 Phosphatidylinositol 3-Kinases 189
4 3-Phosphoinositide-dependent Protein Kinase-1 194
5 Protein Kinase B 197
6 Mammalian Target of Rapamycin 201
7 Other Medicinal Chemistry Approaches to Block the Survival Pathway 203
8 PI3K/PKB Pathway Modulators with Unknown Mechanism of Action 208
9 Conclusions and Outlook 210
References 211
Progress in the Development of Agents to Control the Cell Cycle 218
1 Introduction 220
2 Cyclin-Dependent Kinases 220
3 Aurora Kinases 262
4 Polo-Like Kinases 280
5 Conclusion 291
References 292
HDAC Inhibition in Cancer Therapy: An Increasingly Intriguing Tale of Chemistry, Biology and Clinical Benefit 304
1 Introduction 306
2 Biochemistry of the Histone Deacetylases and Histone Acetyl Transferases 307
3 HDAC Inhibitors 311
4 Clinical Experience with HDAC Inhibitors 328
5 Perspectives and Conclusion 335
References 337
Development of Angiogenesis Inhibitors to Vascular Endothelial Growth Factor Receptor 2 for Cancer Therapy 344
1 Introduction 346
2 Vascular Endothelial Growth Factor and Its Receptors 346
3 Vascular Endothelial Growth Factor Receptor-2 348
4 Future Perspective 379
References 380
Novel Small-Molecule Inhibitors of Src Kinase for Cancer Therapy 394
1 Introduction 395
2 Src Kinase Genetics and Signal Transduction 397
3 Src Kinase Inhibitor: Structural Biology and Drug Design 399
4 Src Kinase Inhibitor: Chemical Diversity and Biological Properties 402
5 Src Kinase Inhibitor: Drug Development for Cancer Therapy 410
6 Concluding Remarks 410
References 411
Bcr-Abl Kinase Inhibitors 418
1 Bcr-Abl: The Hallmark of Chronic Myelogenous Leukemia (CML) 419
2 Imatinib, a Bcr-Abl Kinase Inhibitor Effective in Treating CML 420
3 New Bcr-Abl Kinase Inhibitors 422
4 Dual Inhibitors of Bcr-Abl and Src Kinases 429
5 Key Issues 443
6 Present Status and Future Outlook 446
References 448
Author Index Volume 1 456
Subject Index 458