BOOK
Small-molecule Transcription Factor Inhibitors in Oncology
Khondaker Miraz Rahman | David E Thurston
(2018)
Additional Information
Book Details
Abstract
Oncogenic transcription factors are an increasingly important target for anticancer therapies. Inhibiting these transcription factors could allow tumour cells to be "reprogrammed", leading to apoptosis or differentiation from the malignant phenotype. As the use of kinase inhibitors is gradually declining, transcription factor inhibition is the next hot topic for oncology research and merits much attention. This book highlights recent progress in the development of small-molecule inhibitors of oncogenic transcription factors. It also presents the evidence that this important protein class can be modulated in a number of ways to develop novel classes of therapeutic agents. The broad range of aspects covered by the book is noteworthy and renders it enormously valuable. This title serves as a unique reference book for postgraduates, academic researchers and practitioners working in the fields of biochemistry, biotechnology, cell and molecular biology and bio-inorganic chemistry.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Preface | vii | ||
| Contents | xi | ||
| Chapter 1 Synthetic Approaches and Challenges to Transcription Factor Inhibitors | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Cyclin-Dependent Kinase Inhibitors—Flavopiridol | 2 | ||
| 1.3 Inhibitors of STAT3 and STAT5 | 7 | ||
| 1.4 Inhibitors of c-Myc | 11 | ||
| 1.5 Inhibitors of HIF-1 | 16 | ||
| 1.6 Inhibitors of NF-κB and NF-Y | 21 | ||
| 1.6.1 Tandem Deprotection–Cyclisation Strategy to Produce PBDs | 23 | ||
| 1.6.2 Tandem Reduction–Cyclisation to Produce PBDs | 24 | ||
| 1.6.3 Oxidative Approaches to Produce PBDs | 24 | ||
| 1.6.4 Solid-Phase Synthesis to Produce PBDs | 26 | ||
| 1.6.5 Synthesis of PBD-type Dilactams | 26 | ||
| 1.6.6 Regioselective Reduction of PBD-type Dilactams | 28 | ||
| 1.6.7 Intramolecular Cycloadditions to Access Novel PBDs | 30 | ||
| 1.7 Diversity-oriented Synthesis as a Method for Identifying Novel Inhibitors | 32 | ||
| 1.8 Conclusion | 37 | ||
| References | 38 | ||
| Chapter 2 Computational Approaches in the Development of Small-molecule Transcription Factor Inhibitors | 42 | ||
| 2.1 Introduction | 42 | ||
| 2.2 NF-κB | 44 | ||
| 2.2.1 Docking and Virtual Screening in the Discovery of NF-κB Inhibitors | 45 | ||
| 2.2.2 QSAR | 47 | ||
| 2.2.3 Molecular Dynamics Simulations | 49 | ||
| 2.3 STAT3 | 50 | ||
| 2.3.1 Docking and Virtual Screening | 51 | ||
| 2.4 Conclusion | 52 | ||
| References | 52 | ||
| Chapter 3 Natural Products as Promising Leads Against Oncogenic Transcription Factors and Associated Signalling Pathways | 55 | ||
| 3.1 Introduction | 55 | ||
| 3.2 Natural Leads Targeting NF-κB | 56 | ||
| 3.2.1 Molecular Targeting of the NF-κB Pathway | 57 | ||
| 3.3 Natural Leads Targeting STAT3 | 63 | ||
| 3.3.1 Natural Inhibitors of STAT3 Phosphorylation | 64 | ||
| 3.3.2 Natural Inhibitors of STAT3 Dimerization | 66 | ||
| 3.3.3 Natural Inhibitors of STAT3–DNA Interaction | 67 | ||
| 3.4 Natural Leads Targeting HIF-1 | 68 | ||
| 3.4.1 Natural Leads Promoting HIF-1α Degradation | 68 | ||
| 3.4.2 Natural Leads Suppressing Transcriptional Activity of HIF-1 | 70 | ||
| 3.4.3 Natural Leads Downregulating HIF-1α Protein Expression | 72 | ||
| 3.5 Natural Leads Targeting FOXM1 | 72 | ||
| 3.5.1 Targeting FOXM1 Using Small Molecules | 73 | ||
| 3.6 Conclusion | 75 | ||
| Acknowledgements | 75 | ||
| References | 75 | ||
| Chapter 4 Pyrrolobenzodiazepines as Transcription Factor Inhibitors: An Overview | 81 | ||
| 4.1 Transcription Factors and Their Role In Gene Expression | 81 | ||
| 4.2 Transcription Factors as Mediators of Carcinogenesis | 83 | ||
| 4.3 Targeting Transcription Factors: Proceeding With Caution | 85 | ||
| 4.4 PBDs as Potential Transcription Factor Inhibitors | 86 | ||
| 4.5 Distamycin-based PBD Transcription Factor Inhibitors: One Small Step | 89 | ||
| 4.6 Distamycin-based PBD Transcription Factor Inhibitors: The Next Generation | 92 | ||
| 4.7 Heterocyclic and Benzofusion-based PBD-basedTranscription Factor Inhibitors: Further Improvement | 96 | ||
| 4.8 Alternate PBD-hybrid Transcription Factor Inhibitors | 108 | ||
| 4.9 Conclusion | 114 | ||
| References | 115 | ||
| Chapter 5 Small Molecule Inhibitors of NF-κB and Their Therapeutic Potential in Leukaemia | 125 | ||
| 5.1 Introduction | 125 | ||
| 5.2 The Role of NF-κB in Haematological Malignancies | 126 | ||
| 5.2.1 NF-κB in Myeloid Malignancies | 126 | ||
| 5.2.2 NF-κB in Lymphoid Malignancies | 128 | ||
| 5.3 NF-κB and Drug Resistance | 131 | ||
| 5.4 Therapeutic Targeting of NF-κB | 132 | ||
| 5.4.1 Pharmacological IKK Inhibitors | 132 | ||
| 5.4.2 Non-steroidal Anti-inflammatory Drugs | 133 | ||
| 5.4.3 Curcumin | 133 | ||
| 5.4.4 Parthenolide Analogues | 133 | ||
| 5.4.5 Competitive DNA Binding Inhibitors | 134 | ||
| 5.4.6 Targeting NF-κB Regulated Genes | 134 | ||
| 5.5 Conclusion | 134 | ||
| References | 135 | ||
| Chapter 6 Targeting Signal Transducer and Activator of Transcripion (STAT) 3 with Small Molecules | 147 | ||
| 6.1 Introduction | 147 | ||
| 6.1.1 STAT Structure | 147 | ||
| 6.1.2 STAT Activation and Activity | 149 | ||
| 6.1.3 STAT3 as a Target for Cancer Treatment | 150 | ||
| 6.2 Small-molecule STAT3 Inhibitors | 151 | ||
| 6.2.1 Phosphate-ester-containing Inhibitors | 151 | ||
| 6.2.2 S3I-201 | 151 | ||
| 6.2.3 Inhibitors Based on 4-Aminosalicylic Acid | 152 | ||
| 6.2.4 Inhibitors Based on 5-Aminosalicylic Acid | 154 | ||
| 6.2.5 Celecoxib | 155 | ||
| 6.2.6 Pyrazole-based Inhibitors | 155 | ||
| 6.2.7 Quinolinecarboxamides | 156 | ||
| 6.2.8 Curcumin-derived Inhibitors | 158 | ||
| 6.2.9 Anthraquinone Inhibitors | 158 | ||
| 6.2.10 Inhibitors Based on 2-Aminopyridine | 158 | ||
| 6.2.11 Unsaturated Pyrroldin-2-one Inhibitors | 159 | ||
| 6.2.12 Niclosamide | 160 | ||
| 6.2.13 Purine-based STAT3 Inhibitors | 160 | ||
| 6.2.14 OPB-31121 | 161 | ||
| 6.3 Peptide, Oligonucleotide and Organometallic STAT3 Inhibitors | 161 | ||
| 6.3.1 Peptides and Peptidomimetics | 161 | ||
| 6.3.2 Oligonucleotides | 164 | ||
| 6.3.3 Organometallic Complexes | 164 | ||
| 6.4 Conclusions | 165 | ||
| References | 165 | ||
| Chapter 7 Targeting Promoter G-Quadruplexes for Transcriptional Control | 169 | ||
| 7.1 G-Quadruplex Formation within the Genome | 169 | ||
| 7.1.1 Telomeres and G4s | 170 | ||
| 7.1.2 Intracellular G4s Throughout the Genome | 171 | ||
| 7.1.3 G4 Complexity | 173 | ||
| 7.2 Drug Discovery Efforts via Ligand-based G4 Stabilization | 173 | ||
| 7.2.1 A Historical Perspective | 173 | ||
| 7.2.2 Mucking with MYC | 173 | ||
| 7.2.3 The RAS Gene Family | 177 | ||
| 7.2.4 Bcl-2: To Die or Not to Die? | 179 | ||
| 7.3 Where Do We Go from Here? | 180 | ||
| References | 181 | ||
| Subject Index | 194 |