New Frontiers in Chemical Biology -- Contents -- Chapter 1 The Chemical Genetic Approach: The Interrogation of Biological Mechanisms with Small Molecule Probes -- 1.1 Introduction to Chemical Genetics -- 1.1.1 Forward and Reverse Chemical Genetics -- 1.1.2 Screening Small Molecule Libraries: Some General Considerations -- 1.2 Synthetic Strategies for Exploring Biologically Relevant Chemical Space -- 1.2.1 Synthesis of Compound Libraries with High Substitutional Diversity -- 1.2.2 Synthesis of Compound Libraries with High Stereochemical Diversity -- 1.2.3 Synthesis of Compound Libraries with High Scaffold Diversity -- 1.2.4 Emerging Approaches for Ligand Discovery Using Large Small Molecule Libraries -- 1.3 Discovery of Small Molecule Probes -- 1.3.1 Discovery of Small Molecule Probes Using a Reverse Chemical Genetic Approach -- 1.3.2 The Forward Chemical Genetic Approach -- 1.4 Case Study: Interrogation of the Sonic Hedgehog Pathway Using Complementary Small Molecule Probes -- 1.5 Summary and Outlook -- References -- Chapter 2 Applications for Activity-based Probes in Drug Discovery -- 2.1 Background -- 2.1.1 Introduction -- 2.1.2 Activity-based Probes -- 2.2 Applications of Activity-based Probes to Drug Discovery -- 2.2.1 Identification and Validation of Drug Targets Using Activity-based Probes -- 2.2.2 Use of Activity-based Probes for Drug Lead Identification and Assessment of Selectivity -- 2.2.3 Use of Activity-based Probes for Assessment of In vivo Pharmacodynamic Properties and Efficacy of Lead Compounds -- 2.2.4 In vivo Imaging Applications -- 2.3 Outlook -- Acknowledgements -- References -- Chapter 3 Targeted Intracellular Protein Degradation as a Potential Therapeutic Strategy -- 3.1 Background -- 3.1.1 Introduction -- 3.1.2 The Ubiquitin-Proteasome System -- 3.1.3 Modulation of Protein Levels in Cells.

3.2 Development of the PROTACs Approach -- 3.2.1 Initial Proof-of-Concept -- 3.2.2 Targeting Tumor-relevant Proteins In vitro and In vivo -- 3.2.3 Development of Cell Permeable PROTACs -- 3.2.4 Development of an All-small Molecule PROTAC -- 3.2.5 Further Exploration of the PROTAC Technique -- 3.3 Outlook -- 3.3.1 Strengths of the PROTAC Technique -- 3.3.2 Potential Applications of the PROTAC Technique -- 3.3.3 Continued Development of the PROTAC Technique -- Acknowledgement -- References -- Chapter 4 Chemical Biology of Stem Cell Modulation -- 4.1 Introduction -- 4.2 Stem Cells: Ontogeny, Characterisation and Clinical Utility -- 4.3 Stem Cell Manipulation In Vitro -- 4.3.1 Small Molecules to Promote Stem Cell Expansion -- 4.3.2 Small Molecules to Direct Stem Cell Differentiation -- 4.3.3 Small Molecules to Promote Dedifferentiation and Transdifferentiation -- 4.4 Stem Cell Manipulation In Vivo -- 4.4.1 Exogenous Stem Cells: Homing, Engraftment and Activation -- 4.4.2 Endogenous Stem Cell Manipulation -- 4.4.3 Stem Cells in Dysplasia: Cancer and Teratogenicity -- 4.5 Conclusions and Future Prospects -- References -- Chapter 5 Chemical Biology of Histone Modifications -- 5.1 Histones, Epigenetics and Chromatin -- 5.1.1 DNA Modifications -- 5.1.2 Euchromatin and Heterochromatin -- 5.1.3 Correlation of Histone Modifications with Transcriptional States -- 5.1.4 Mechanisms by Which Histone Modifications Achieve Transcriptional Regulation -- 5.1.5 Epigenetics -- 5.2 The Lysine Acetylation System -- 5.2.1 Histone Acetyltransferases -- 5.2.2 Histone Deacetylases -- 5.2.3 Bromodomains -- 5.3 The Lysine and Arginine Methylation System -- 5.3.1 Histone Methyltransferases -- 5.3.2 Histone Demethylases -- 5.3.3 Methyl Binding Domains -- 5.4 Serine/Threonine/Tyrosine Phosphorylation of Histones -- 5.5 Lysine Ubiquitylation/SUMOylation/Biotinylation of Histones.

5.6 Appendix: Abbreviations Used in this Chapter -- Acknowledgements -- References -- Chapter 6 Chemologics -- 6.1 Introduction -- 6.2 Synthetic Vaccines -- 6.2.1 Carbohydrate-based Vaccines -- 6.2.2 Purely Synthetic Vaccines -- 6.2.3 Synthetic Virus-like Particles -- 6.2.4 Expanding the Genetic Code and Breaking Self-tolerance -- 6.2.5 Chemically Programmed Vaccination -- 6.3 Antibodies -- 6.3.1 Antibody-directed Therapies -- 6.3.2 Improved Pharmacokinetics -- 6.4 Oligonucleotides -- 6.4.1 Aptamers - Macugen -- 6.4.2 siRNA -- 6.4.3 Locked Nucleic Acids -- 6.5 Conclusions -- References and Notes -- Chapter 7 Antibody-Drug Conjugates in Oncology -- 7.1 Introduction and General Considerations -- 7.2 Calicheamicin Conjugates -- 7.3 Maytansine Conjugates -- 7.4 Auristatin Conjugates -- 7.5 Duocarmycin Conjugates -- 7.6 Miscellaneous Conjugates -- 7.7 Conclusions -- References -- Chapter 8 Drug Discovery by DNA-encoded Libraries -- 8.1 Introduction -- 8.1.1 The Lack of Discovery Tools Interrogating Undrugged Targets -- 8.1.2 Applying Nature's Strategy in Discovering Functional Molecules -- 8.1.3 Topics in this Chapter -- 8.2 DNA-templated library -- 8.2.1 Basic Principles of DNA-templated Organic Synthesis -- 8.2.2 The Development of DNA-templated Libraries -- 8.2.3 The Application of DNA-templated Libraries in Drug Discovery -- 8.3 DNA-recorded Library -- 8.3.1 GSK/Praecis -- 8.3.2 Neri Group/Philochem -- 8.3.3 A DNA-recorded Library by DNA Assembly: ESAC Library -- 8.4 Discussion -- 8.4.1 The Advantages of DNA-encoded Library -- 8.4.2 Prospects and Outlook -- Acknowledgements -- References -- Subject Index.