Small-Molecule Inhibitors of Protein-Protein Interactions (eBook)

Small-Molecule Inhibitors of Protein-Protein Interactions 3
Preface 5
Contents 7
Contributors 9
Hydrogen-Bonded Synthetic Mimics of Protein Secondary Structure as Disruptors of Protein-Protein Interactions 11
1 Introduction 12
2 a-Helix Mimicry 12
2.1 Hamilton´s Oligopyridylamides 15
2.2 Oligobenzamides 16
2.3 Oligobenzamide-Like a-Helix Mimics 18
2.4 Hydrogen-Bonded a-Helix Mimetic Scaffolds 20
3 beta-Strand/beta-Sheet Mimicry 21
3.1 Nowick´s beta-Strand/beta-Sheet Conformational Templates 22
3.2 Hirschmann and Smith´s beta-Strand Mimetics 27
3.3 Hamilton´s Extended beta-Strand Mimetics 29
4 Epilogue 30
References 30
Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied 34
1 Introduction 35
2 IL-2 Biology 38
2.1 Ligand and Receptor Biology 38
2.2 Diseases and Therapies 40
2.2.1 IL-2 Agonists: Oncology and Infectious Disease 40
2.2.2 IL-2Ra Antagonists 40
Allograft Transplantation 41
Autoimmune Disease 42
3 Protein Structures 42
3.1 IL-2 42
3.2 IL-2 Receptor 43
4 IL-2 Small-Molecule Inhibitors 45
4.1 Discovery of Ro26-4550 45
4.2 Structural Characterization of Ro26-4550 and the Importance of Protein Dynamics 45
4.3 Ligand-Binding Potential and Surface Plasticity of IL-2 48
4.4 Medicinal Chemistry Optimization of IL-2 Antagonists: SP4206 50
4.5 Comparison of Small-Molecule and Protein Interactions with IL-2 51
5 Themes from IL-2 Small-Molecule PPI Inhibitors: Lessons Learned and Applied 54
5.1 Target Dynamics and Surface Plasticity 54
5.2 Inhibitable Surface Epitopes 54
5.3 Inhibitor Ligands: Shape, Composition, and Construction 55
5.3.1 Shapes 55
5.3.2 Chemical Character and Ligand Efficiency 56
5.3.3 Cooperativity Through Fragment Linking 57
5.4 Screening and Characterization Tools 58
5.5 Computational Methods 58
6 Conclusions 59
References 60
Small Molecule Inhibitors of the Human Papillomavirus E1-E2 Interaction 69
1 Introduction: Papillomaviruses and Human Disease 70
2 Potential Targets for Drugs Against Human Papillomaviruses 71
3 Assays for Inhibitors of HPV E1/E2 Activities 73
4 Discovery and Optimization of Indanedione-Containing E1-E2 Interaction Inhibitors 76
5 Structure of the Inhibitor-TAD Complex 79
6 Discovery and Optimization of a Second E1-E2 Interaction Inhibitor Series 84
7 Model for the Interaction of Repaglinide-Derived Inhibitors with E2 TAD 88
8 General Conclusions on Discovery of Protein-Protein Interaction Inhibitors 92
References 93
Design of Small-Molecule Smac Mimetics as IAP Antagonists 97
1 IAP Proteins as Key Apoptosis Regulators 98
2 Smac/DIABLO as the Endogenous Antagonist of IAP Proteins 100
3 Structural Basis for the Interaction Between XIAP and Smac Proteins 100
4 Molecular Mechanisms of the Inhibition of Caspase-9 and Caspase-3/-7 by XIAP 101
5 Structure-Activity Relationship of Smac-Based Peptides 102
6 Design of Smac Peptidomimetics 102
7 Structure-Based Design of Conformationally Constrained Nonpeptidic Smac Mimetics 103
8 Design of Bivalent Smac Mimetics Mimicking Natural Smac Protein 105
9 Smac Mimetics Are Not Only XIAP Inhibitors 109
10 Design of Selective IAP Inhibitors 110
11 Smac Mimetics as Single Agents for Cancer Treatment 110
12 Mechanism of Action of Smac Mimetics in Apoptosis Induction 112
13 Smac Mimetics Used in Combination with Other Agents for Cancer Treatment 113
14 Advantages and Disadvantages of Monovalent and Bivalent Smac Mimetics for Development of Therapeutic Agents 114
15 Smac Mimetics in Clinical Development for Cancer Treatment 115
16 Beyond Apoptosis 116
17 Summary 116
References 118
Small-Molecule Inhibitors Reveal a New Function for Bcl-2 as a Proangiogenic Signaling Molecule 122
1 Introduction 123
2 The Bcl-2 Family 124
2.1 Apoptotic Bcl-2 Control Points 125
2.2 Bcl-2 Family Interactions at the Mitochondria 125
2.3 Bcl-2 and Tumor Angiogenesis 126
3 Nonpeptidic Small-Molecule Inhibitors of Bcl-2 127
3.1 Nature´s Bounty 128
3.1.1 Gossypol/AT-101 128
3.1.2 Antimycin A 130
3.1.3 Tea Polyphenols 131
3.2 Products of the Laboratory 131
3.2.1 Obatoclax 131
3.2.2 ABT-737 132
3.2.3 ABT-263 133
3.2.4 TW-37 134
3.2.5 HA14-1 136
3.3 Bcl-2 Inhibitors and Tumor Angiogenesis 136
3.4 The Influence of Choice of Ligands on the Drug Discovery Process 137
4 Conclusion 138
References 139
Small-Molecule Modulators of c-Myc/Max and Max/Max Interactions 145
1 Introduction 145
2 Inhibitors of Myc/Max Interactions 146
3 Stabilizers of Max/Max Interactions 151
4 Concluding Remarks 153
References 154
Small-Molecule Inhibitors of the p53-MDM2 Interaction 156
1 The p53 Tumor Suppressor as a Target for Pharmacological Activation 157
1.1 MDM2: A Master Regulator of p53 157
1.2 Inhibitors of p53-MDM2 Binding Can Activate the p53 Pathway 159
2 Small-Molecule MDM2 Inhibitors 159
2.1 Early Efforts on Targeting the p53-MDM2 Interaction 159
2.2 The Nutlins 162
2.2.1 Nutlins as Research Tools 163
2.3 Newer MDM2 Antagonists 165
2.3.1 Small Molecules Targeting p53-MDM2 Binding 165
2.3.2 Molecules Targeting Other Interactions of MDM2 172
3 Therapeutic Strategies Based on Antagonizing p53-MDM2 Binding 172
References 173
Index 178