Protein degradation with new chemical modalities : successful strategies in drug discovery and chemical biology / edited by Hilmar Weinmann and Craig Crew

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.

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.

Medienart:	E-Book

Erscheinungsjahr:	[2021] © 2021
Erschienen:	Cambridge: Royal Society of Chemistry ; 2021 © 2021

Reihe:	RSC drug discovery - 74

Sprache:	Englisch

Beteiligte Personen:	Weinmann, Hilmar [HerausgeberIn] Crews, Craig [HerausgeberIn]

Links:	Volltext [lizenzpflichtig]

ISBN:	978-1-83916-069-1 978-1-83916-077-6

Themen:	Drugs Drugs ; Design Electronic books Proteolysis

Umfang:	1 Online-Ressource (xxi, 359 Seiten) ; Illustrationen

doi:	10.1039/9781839160691

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	169562727X