Inducing targeted protein degradation : from chemical biology to drug discovery and clinical applications / / edited by Philipp Cromm

• Pubblicazione: Weinheim, Germany : , : Wiley-VCH, , [2023]; ©2023
• Descrizione fisica: 1 online resource (387 pages)
• Disciplina: 574.192
• Soggetto topico: Biochemistry; Drug development; Proteolysis
• Persona (resp. second.): CrommPhilipp
• Nota di bibliografia: Includes bibliographical references and index.
• Nota di contenuto: Cover -- Title Page -- Copyright Page -- Contents -- Preface -- Chapter 1 Targeted Protein Degradation - The Story So Far -- 1.1 Introduction to Targeted Protein Degradation (TPD) -- 1.1.1 What Can Be Expected from this Book? -- 1.2 Development of Targeted Protein Degradation: Chronology and Milestones -- 1.2.1 Milestone 1: Early Monovalent Protein Degraders - The Surprising Biology of Fulvestrant -- 1.2.2 Milestone 2: The First PROTACs - From Peptidic Degraders to Chemical Biology Tools -- 1.2.3 Milestone 3: Improving Drug-Like Properties - SNIPERs and Peptidomimetic VHL Binders -- 1.2.4 Milestone 4: PROTACs on the Rise - Small-Molecule Degraders Achieve in vivo PoC -- 1.2.5 Milestone 5: Sticking It to the Man! Molecular Glues -- 1.2.6 Milestone 6: Human After All - TPD in Clinical Trials -- 1.2.7 Milestone 7: Beyond the Proteasome - Inducing Proximity to Modulate Protein Levels -- 1.2.7.1 Is TPD Just the Beginning? Bifunctional Modulators ofPost-transcriptional Modification -- 1.3 Conclusion and Outlook -- References -- Chapter 2 Cellular Principles of Targeted Protein Degradation -- 2.1 Basic Principles of Targeting Substrates to the Proteasome and Lysosomes -- 2.1.1 Ubiquitin-Proteasome System (UPS) -- 2.1.2 Lysosomal Targeting -- 2.2 Targeted Protein Degradation from the Cytosol and the Nucleus -- 2.2.1 Targeting to the Proteasome -- 2.2.1.1 Regulatory Target Recruitment -- 2.2.1.2 Target Engagement by the Ubiquitination Machinery -- 2.2.1.3 Engaging the Proteasome -- 2.2.2 Targeting to Lysosomes -- 2.3 Targeted Degradation from Membrane-Enclosed Organelles and the Extracellular Space -- 2.3.1 Degradation from the Plasma Membrane (PM) and the Extracellular Space -- 2.3.1.1 Internalization at the PM and Endosomal Sorting -- 2.3.1.2 Ubiquitination at the PM -- 2.3.2 Degradation from the Endoplasmic Reticulum (ER). ; 2.3.2.1 ER-Associated Protein Degradation (ERAD) - ProteoasomalDegradation from the ER -- 2.3.2.2 ER Lysosome-Associated Degradation (ERLAD) -- 2.3.3 Degradation from the Golgi -- 2.4 Concluding Remarks -- Acknowledgments -- References -- Chapter 3 E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development -- 3.1 Introduction -- 3.1.1 Ubiquitin Code and Targeted Protein Degradation -- 3.1.2 General Concepts of E3 Ligase Mechanism and Regulation -- 3.2 Substrate Recruitment and Degron Recognition -- 3.2.1 Regulating E3 Ligases Activity -- 3.3 RING E3 Ligases -- 3.3.1 Definition and Discovery -- 3.3.2 Subgroups -- 3.3.3 Insights into RINGs Regulation and Function -- 3.4 HECT E3 Ubiquitin Ligases -- 3.4.1 Definition and Discovery -- 3.4.2 Subgroups -- 3.4.3 Structure and Mechanism -- 3.4.4 Regulation -- 3.4.4.1 Intramolecular Interactions -- 3.4.4.2 Intermolecular Interactions -- 3.4.4.3 Post-translational Modifications -- 3.4.5 Insights into Hect Functions -- 3.4.5.1 Growth Signaling -- 3.4.5.2 Immunity -- 3.5 RING-IBR-RING (RBR) -- 3.5.1 Structure and Mechanism -- 3.5.2 Insights into Their Regulation and Function -- 3.6 Conclusion and Insights into Drug Development -- References -- Chapter 4 A Structural and Biophysical Perspective of Degrader Activity Through Ternary Complex Formation -- 4.1 Introduction -- 4.1.1 Mechanism of Degraders Through Ternary Complexes -- 4.1.2 Ternary Complex Behavior -- 4.1.2.1 Binding Pose -- 4.1.2.2 Affinity and Cooperativity -- 4.1.2.3 Stoichiometry -- 4.1.2.4 Residency -- 4.1.2.5 Plasticity -- 4.1.2.6 Flexibility -- 4.1.3 Observing and Quantifying Ternary Complex Behavior -- 4.1.3.1 Biophysics -- 4.1.3.2 Structural Biology -- 4.2 X-ray Crystal Structures of Ternary Complexes -- 4.2.1 PROTAC-Induced Ternary Complex Structures -- 4.2.1.1 PROTACs Recruiting von Hippel-Lindau Protein (VHL). ; 4.2.1.2 PROTACs Recruiting Other E3 Ligases -- 4.2.1.3 Assessment of Structure-Guided Design of PROTAC Degraders -- 4.2.2 Molecular-Glue-Induced Ternary Complex Structures -- 4.2.2.1 Molecular Glues Recruiting Cereblon (CRBN) -- 4.2.2.2 Molecular Glues Recruiting Other E3 Ligases -- 4.3 Future Perspective on the Importance of Ternary Complexes in PROTAC Discovery and Development -- 4.3.1 Ternary Complexes - Is Seeing Believing? -- 4.3.2 Each (Ternary Complex) to Its Own -- References -- Chapter 5 Computational Modeling of PROTAC Ternary Complexes and Linker Design -- 5.1 Introduction -- 5.2 PROTAC Ternary Complexes -- 5.3 Computational Modeling of PROTAC Ternary Complexes -- 5.4 PROTAC Design and Optimization -- 5.5 Emerging Methods for Computationally Designing and Optimizing PROTACs -- 5.6 Looking into the Future -- Acknowledgments -- References -- Chapter 6 Molecular Glue Degraders: From Serendipity to Hunting and Design -- 6.1 Introduction -- 6.2 "Molecular Glue" Concept -- 6.2.1 Natural Compounds -- 6.2.1.1 Molecular Glues -- 6.2.1.2 Molecular Glue Degraders -- 6.2.2 Synthetic Compounds -- 6.2.2.1 Molecular Glues -- 6.2.2.2 Molecular Glue Degraders -- 6.3 Synthetic Molecular Glue Degraders: Serendipitous Discoveries -- 6.3.1 Molecular Glue Degraders Hijacking CRL4 (IMiDs): Broad Target Accommodation -- 6.3.2 Molecular Glue Degraders Hijacking CRL4 (Aryl Sulfonamides): High Shape Complementarity -- 6.3.3 BCL6 Degraders: Induction of Polymerization -- 6.4 Synthetic Molecular Glue Degraders: Intentional Developments -- 6.4.1 β-Catenin Molecular Glue Degraders -- 6.4.2 Cyclin K Molecular Glue Degraders -- 6.4.3 Prospective Discovery of IKZF1 Molecular Glue Degraders via "Up Assays" -- 6.4.4 Structure-Guided Development of Helios (IKZF2) Molecular Glue Degraders -- 6.4.5 Discovery of VHL-Binding Molecular Glue Degraders -- 6.5 Conclusions and Outlook. ; Acknowledgments and Funding -- Conflict of Interest Statement -- References -- Chapter 7 Targeted Protein Degradation as a Therapeutic Strategy in Neurodegenerative Diseases -- 7.1 Introduction -- 7.2 Heterobifunctional Targeted Protein Degraders -- 7.2.1 Misfolded Proteins -- 7.2.1.1 Tau -- 7.2.1.2 Alpha-Synuclein -- 7.2.1.3 mHtt -- 7.2.2 TDP-43 -- 7.2.3 Kinases and HDACs -- 7.3 Molecular Glues -- 7.4 Conclusion -- Declaration of Interest -- References -- Chapter 8 Insights and Future Perspectives of Covalent Protein Degraders -- 8.1 Introduction -- 8.2 Protein Degraders that Covalently Interact with the Substrate Proteins -- 8.2.1 HaloPROTAC -- 8.2.2 METAP2 and BTK -- 8.2.3 KRAS G12C -- 8.2.4 EGFR, ERK1/2, and ERRα -- 8.2.5 Monofunctional Protein Degraders -- 8.3 Protein Degraders that Covalently Interact with E3 Ubiquitin Ligases -- 8.3.1 RNF4 -- 8.3.2 RNF114 -- 8.3.3 KEAP1 -- 8.3.4 FEM1B -- 8.3.5 SPSB2 -- 8.3.6 DCAF16 -- 8.3.7 DCAF11 -- 8.4 Technologies for Covalent Protein Degrader Discovery -- 8.5 Outlook of Leveraging Covalent Chemistry for Targeted Protein Degradation -- Acknowledgment -- References -- Chapter 9 Extending the Degradation Toolkit - mRNA Targeting as an Alternative Means to Affect Protein Levels -- 9.1 Introduction -- 9.2 Life Cycle of Eukaryotic mRNAs -- 9.3 Splicing Shapes the Cell's Transcriptome -- 9.3.1 Aberrant Splicing Impacts the Transcriptome -- 9.3.2 Therapeutic Strategies to Change Protein Levels Through Splicing Regulation -- 9.3.2.1 Activating a Weak Splice Site in SMN2 to Increase Protein Production -- 9.3.2.2 mRNA Degradation of HTT by Inducing Aberrant Splicing in HD -- 9.3.2.3 Modulating the MKNK2 Isoform Balance with Splice Switching Oligonucleotides (SSOs) -- 9.3.2.4 Targeting Global AS with a Molecular "Glue" that Degrades RBM39 -- 9.3.2.5 PROTAC-Mediated Degradation of Splicing Factor 3B1 (SF3B1). ; 9.3.3 Nuclear RNA Decay -- 9.3.3.1 Small-Molecule-Mediated Nuclear Decay of CUG Repeat Expansions -- 9.4 Cytoplasmatic RNA Quality Control Mechanisms -- 9.4.1 Incorrect Splicing Triggers NMD in the Cytoplasm -- 9.4.1.1 Harnessing Intronic Poly(A) Activation with ASOs -- 9.4.2 RNA Binding Proteins Recruit the mRNA Degradation Machinery -- 9.4.2.1 RNA-PROTAC-Mediated Degradation of LIN28A and RBFOX1 -- 9.4.3 RNA Interference (RNAi) - microRNA, siRNA, and ASO Gapmers -- 9.4.3.1 Small-Molecule Enhancement of microRNA Processing -- 9.4.3.2 SMOL-Mediated Upregulation of miR-124 in Inflammatory Diseases -- 9.4.3.3 RIBOTAC-Mediated Degradation of Pre-miR-21 via Targeted Recruitment of RNase L -- 9.5 Conclusions -- Acknowledgments -- Conflict of Interest -- References -- Chapter 10 The Future of Heterobifunctional Compounds: PROTACs and Beyond -- 10.1 Introduction -- 10.2 Protein Degradation Beyond Cancer -- 10.3 Emerging Heterobifunctional Modalities for Protein Degradation -- 10.3.1 PROTAC Variations -- 10.4 PROTAC-Inspired Technologies -- 10.5 Highjacking Autophagy -- 10.6 Degradation of Extracellular Proteins -- 10.7 Heterobifunctional Compounds Beyond Protein Degradation -- 10.8 Degradation of RNA -- 10.9 Modulating Phosphorylation -- 10.10 Targeted Acetylation -- 10.11 Potential Applications of Heterobifunctional Compounds to Modulate PTMS -- 10.12 Conclusions and Outlook -- References -- Chapter 11 Destruction with a Purpose: Targeted Protein Degradation in Drug Discovery -- 11.1 PROTACs in Drug Discovery: Why? -- 11.1.1 Targeting Proteins that Do Not Respond to Inhibition -- 11.1.2 Selective Inhibition of Isoforms -- 11.1.3 Increase in Potency Because of Catalytic Activity -- 11.1.4 Prolonged Duration of Effects -- 11.2 Routes of Application for PROTACs -- 11.3 Tackling DMPK Challenges of PROTACs. ; 11.4 Molecular Glue Degraders: Definition, Advantages, and Challenges.
• Titolo autorizzato: Inducing targeted protein degradation
• ISBN: 3-527-83620-9; 3-527-35017-9
• Formato: Materiale a stampa
• Livello bibliografico: Monografia
• Lingua di pubblicazione: Inglese
• Record Nr.: 9910830502003321
• Lo trovi qui: Univ. Federico II