Protein degradation with new chemical modalities : successful strategies in drug discovery and chemical biology /

This book provides a comprehensive overview from the leading academic and industrial experts on recent developments, scope and limitations in this dynamically growing research area; an ideal reference work for researchers in drug discovery and chemical biology as well as advanced students.

Bibliographic Details
Other Authors:	Crews, Craig (Editor), Weinmann, Hilmar (Editor)
Format:	eBook
Language:	English
Published:	Cambridge : Royal Society of Chemistry, 2020.
Series:	RSC drug discovery series ; 74.
Subjects:	Drugs > Design. Proteolysis. Electronic books.
Online Access:	Connect to the full text of this electronic book

Table of Contents:

Cover
Half Title
Series Information
Title Page
Copyright Page
Preface
Contents
Chapter 1 PROTAC-mediated Target Degradation: A Paradigm Changer in Drug Discovery?
References
Chapter 2 Structural and Biophysical Principles of Degrader Ternary Complexes
2.1 Introduction
2.1.1 Mechanistic Advantages of Targeted Protein Degradation
2.1.1.1 Immediate Advantages of Degradation Versus Inhibition
2.1.1.2 Differentiation of Degraders due to Their Mode of Action
2.1.2 History of PROTACs (2001-2010)
2.1.3 Small-molecule VHL- and CRBN-based PROTACs (2010-2015)
2.2 Structural Features of Ternary Complexes
2.2.1 Ternary Complex Equilibria and Definitions
2.2.2 Structural Elucidation of PROTAC Ternary Complexes
2.2.2.1 The First PROTAC Ternary Complex Crystal Structure: VHL:MZ1:Brd4BD2
2.2.2.2 Structure-guided design of SMARCA2/4 PROTACs
2.2.2.3 Ternary Structures of CRBN-based PROTACs
2.2.3 Degraders as Monovalent Molecular Glues
2.2.3.1 Cereblon-targeting Immunomodulatory Drugs
2.2.3.2 DCAF15-targeting Sulfonamide Drugs
2.2.4 Surface Areas Buried by PROTACs and Monovalent Glues
2.3 Ternary Assays
2.3.1 Can My PROTAC Form a Ternary Complex?
2.3.1.1 Pull-down Assays
2.3.1.2 Proximity-based Ternary Assays: AlphaScreen/LISA and TR-FRET
2.3.1.3 Surface Plasmon Resonance
2.3.2 How Tightly Does My Ternary Complex Bind?
2.3.2.1 Competition Assays
2.3.2.2 Direct Binding Assays
2.3.3 To What Extent Is My Ternary Complex Cooperative?
2.3.4 How Long Does My Ternary Complex Last?
2.3.5 Does the PROTAC Induce Ternary Complex Formation in Cells?
2.3.5.1 Separation of Phases-based Protein Interaction Reporter Assay (SPPIER)
2.3.5.2 Bioluminescence Resonance Energy Transfer (BRET)
2.4 Concluding Remarks
2.5 Acknowledgments
2.5.1 Funding
2.5.2 Conflict of Interest Statement
References
Chapter 3 Immediate and Selective Control of Protein Abundance Using the dTAG System
3.1 The Potential and Limitations of Targeted Protein Degradation
3.2 Chemical-Genetic Degradation Approaches
3.3 Development of the dTAG Platform
3.4 Genetic Methods to Express FKBP12F36V-fusions
3.4.1 Ectopic Expression of FKBP12F36V-fusions
3.4.2 Knock-in Strategies to Express FKBP12F36V-fusions
3.5 Strategies Towards Identification of a Lead dTAG Molecule
3.5.1 Biochemical Assays for FKBP12F36V and E3 Ligase Binding
3.5.2 Determining FKBP12F36V-specific Degradation in Cells
3.5.3 Requirement of E3 Ligase and Proteasome
3.5.4 Assessment of dTAG Molecule Selectivity
3.5.5 In Vivo Assessment of dTAG Molecule Activity
3.6 Case Studies Employing the dTAG Platform
3.6.1 Target Validation Using dTAG
3.6.2 Targeting Recalcitrant Oncoproteins Using dTAG
3.6.3 Targeting Essential Transcriptional Regulators Using dTAG