Pharmacology of the WNT Signaling System

Description

This book reflects the state of the art of our understanding of the WNT signaling system, which comprises a network of signaling pathways initiated by the secreted WNT lipoglycoproteins, which are crucial for embryonal development, stem cell regulation, tissue homeostasis and repair. Dysfunction of this evolutionarily conserved signaling system leads to many diseases including developmental disorders, diverse forms of cancer, fibrosis, neurodegenerative disease and many more. The WNT signaling system is built upon 19 mammalian, secreted WNT lipoglycoproteins that interact with a plethora of distinct receptors, such as the G protein-coupled receptors called Frizzleds (FZD1-10), LDL receptor-like proteins (LRP5/6), receptor tyrosine kinases (ROR1, 2, RYK and PTK7). In addition, WNT pathways are tightly regulated by many secreted and cell-intrinsic negative regulators, such as soluble FZD-related proteins (SFRPs), Dickkopfs (DKKs), WNT-inhibitory proteins, TIKI, RNF43 and more. Understanding the basic mechanism in terms of receptor-ligand interaction, receptor selectivity, signal initiation and desensitization remain poorly understood, even though substantial advances have been made the recent years. Due to the involvement of the WNT signaling system in human disease, it appears obvious to target diverse branches pharmacologically and therapeutically. However, given the complexity of the system and its importance for stem cell regulation and tissue maintenance, therapy comes with obvious risks for severe side effects. The field is addressing the challenge to identify suitable targets and selective compounds for therapy allowing disease-selective therapeutic effects and balancing unwanted side effects. This book summarizes the current understanding of the basic and applied pharmacology in the WNT signaling system and bridges disciplines such as pharmacology, physiology, neurosciences, oncology and drug development. Preface References Contents Part I: Basic Pharmacological Principles of the WNT Signaling System Controlling Wnt Signaling Specificity and Implications for Targeting WNTs Pharmacologically 1 Introduction 2 Wnt Processing and Secretion 3 Wnt Signaling 4 Wnt Signaling Specificity 5 Engineered Specificity 6 Targeting Wnt in Disease 6.1 Cancer 6.2 Tissue Regeneration and Repair 7 Concluding Remarks References Extracellular WNTs: Trafficking, Exosomes, and Ligand-Receptor Interaction 1 Introduction 2 Impact of Extracellular Forms of WNTs on Signaling 3 Receptor Binding 4 Is There a WNT Signaling Feedback in WNT Secretion? 5 Critical Studies of Exosomal WNTs 6 Conclusion References LRPs in WNT Signalling 1 Historical Perspective/Timeline 2 Structural and Functional Features of LRP5/6 2.1 The LRP5/6 ECD 2.2 The LRP5/6 ICD 3 LRP6 Signalosomes 4 LRP5/6 and Disease 4.1 Bone Diseases 4.2 Eye Disease 4.3 Coronary Artery Disease 4.4 Alzheimer´s Disease 4.5 Parathyroid Tumours 5 LRP4 6 Pharmacological Tools Targeting LRPs in WNT/β-Catenin Signalling 7 Antibody Tools 7.1 Anti-Sclerostin mAbs 7.2 Anti-DKK1 mAbs 7.3 Anti LRP5/6 mAbs 8 WNT Surrogates References Targeting the Receptor Tyrosine Kinase ROR1 by Small Molecules 1 Introduction 2 RTKs Function and Structure 3 Receptor Tyrosine Kinase-Like Orphan Receptors 1 (ROR1) 3.1 ROR1 Structure and Function 3.2 ROR1 Tyrosine Kinase Activity 3.3 ROR1 Expression During Embryogenesis and in Normal Adult Tissues 3.4 ROR1 and Cancer 3.5 ROR1 Isoforms in Cancer 3.6 Therapeutic Targeting of ROR1 3.7 Small Molecule Inhibitors of ROR1 Tyrosine Kinase 3.7.1 KAN0439834 and KAN0441571C 3.7.2 ARI-1 3.7.3 Strictinin 4 Conclusions References Employing Genetically Encoded, Biophysical Sensors to Understand WNT/Frizzled Interaction and Receptor Complex Activation 1 Introduction 2 Dissection of Signaling Mechanisms 3 Sensors to Understand FZD Pharmacology 4 Small Molecule Binding 5 WNT Binding 6 Sensors of Dynamic Receptor Conformation 7 Sensing the Active Conformation of FZDs 8 Sensing Receptor-Transducer Interaction and Activation 9 Conclusions and Therapeutic Perspectives References Can We Pharmacologically Target Dishevelled: The Key Signal Transducer in the Wnt Pathways? 1 Introduction 2 Wnt Signalling-Related Diseases 2.1 Wnt Signalling Upstream of DVL and Related Diseases 2.2 DVL-Related Diseases 3 Potential for Pharmacological Modulation of DVL 3.1 Inhibition of DVL Phosphorylation 3.2 PDZ Inhibitors 3.3 Inhibition of DVL Oligomerization 3.4 DEP Domain Inhibition 3.5 Stimulation of DVL Degradation 3.6 Inhibition of DVL Dephosphorylation References Zooming in on the WNT/CTNNB1 Destruction Complex: Functional Mechanistic Details with Implications for Therapeutic Targeting 1 Introduction 2 WNT Off: Destruction Complex Function 2.1 Partners, Interactions, and Levels 2.2 Destruction Complex Oligomerization and Multivalency 3 WNT On: Inactivation of the Destruction Complex 3.1 Signalosome Formation 3.1.1 WNT Protein Binding to FZD and LRP5/6 3.1.2 DVL Recruitment 3.1.3 LRP5/6 Phosphorylation 3.2 Inactivation of the Destruction Complex 3.2.1 AXIN 3.2.2 APC 3.2.3 GSK3 3.2.4 CSNK1A1 3.2.5 CTNNB1 4 Targeting CTNNB1 and the Destruction Complex in Cancer 4.1 Hyperactivation of WNT/CTNNB1 Signaling 4.2 Therapeutic Targeting 4.2.1 Natural Compounds 4.2.2 High-Throughput Chemical Screens 4.2.3 Rational Design 5 Summarizing Conclusion References An Overview of Potential Therapeutic Agents Targeting WNT/PCP Signaling 1 Introduction 2 Potential Therapeutic Agents Targeting WNT/PCP Signaling 2.1 Targeting all WNTs (Porcupine Inhibitors and Others) 2.2 WNT5A 2.3 sFRPs (Secreted Frizzled-Related Proteins) 2.4 Frizzled Inhibitors 2.5 RORs Inhibitors 2.6 VANGL2 and p62/SQSTM1 Interaction Inhibitor: p62DN 2.7 Protein Tyrosine Kinase 7 (PTK7) Inhibitors 2.8 Receptor Like Tyrosine Kinase (RYK) Inhibitor 2.9 DVL Inhibitors 2.10 Casein Kinase 1 (CK1) Inhibitor 2.11 Downstream RHO-ROCK and RAC-JNK Pathway Inhibitors 3 Conclusion and Outlook References Mining Natural Compounds to Target WNT Signaling: Land and Sea Tales 1 Introduction 2 Assay Development 3 Natural Products as a Renewed Source of Drug Candidates 4 Species Collection, Extraction, and Screening in the Search of Natural WNT Modulators 5 Fractionation and Compound Identification in the Search of Natural WNT Modulators 6 Identification of the Molecular Target of the Natural WNT Modulators 7 In Vivo Anticancer Properties of WNT Pathway Inhibitors from Natural Sources 8 Medicinal Chemistry Optimization of the Natural Compounds Targeting WNT Signaling 9 Conclusions and Perspectives References Part II: Disease-Specific Targeting of the WNT Signaling System Frizzled7 Activates β-Catenin-Dependent and β-Catenin-Independent Wnt Signalling Pathways During Developmental Morphogenesis: ... 1 Introduction 2 Knowledge Gained from Developmental Morphogenesis in Lower Organisms 3 Frizzled7 Signalling in Developmental Contexts 4 Frizzled7 Function in the Gut and Colorectal Cancer 4.1 Wnt Signalling in the Intestinal Epithelium and Colorectal Cancer 4.2 Upstream Wnt Signalling in Stem Cells and Cancer 4.3 FZD7 Is a Potent Anti-Cancer Therapeutic Target: Why? 5 Conclusions and Perspectives References Targeting Oncogenic WNT Signalling with WNT Signalling-Derived Peptides 1 Introduction 2 WNT-Related Oncotargets and the Development of Peptide-Based Therapies 2.1 Role of β-Catenin in Cancer 2.1.1 Development of Peptides Antagonizing the β-Catenin/BCL9 Interaction 2.1.2 Development of Peptides Antagonizing the β-Catenin/TCF4 Interaction 2.1.3 Development of a Peptide Antagonizing the β-Catenin/LEF1 Interaction 2.2 Role of the Frizzled Receptor FZD7 in Cancer 2.2.1 Development of Peptides Antagonizing FZD7 Function 2.3 Role of WNT5A in Cancer 2.3.1 Development of a WNT5A-Agonizing Peptide 2.3.2 Development of WNT5A-Antagonizing Peptides 3 Clinical Trials of WNT Signalling-Derived Peptides References WNT Signalling in Lung Physiology and Pathology 1 Introduction 2 Physiology of the Lung: Role of WNT Signalling 2.1 Anatomy of the Lung 2.2 Cell Type: Specific Expression Patterns of WNTs/FZDs 2.3 Lung Development 2.4 Epithelial Cell Specification/Regeneration in Adulthood 2.5 Mesenchymal Cell Specification/Differentiation in Adulthood 3 Pathology: Role of WNT Signalling 3.1 Normal Lung Ageing 3.2 Asthma 3.3 COPD 3.4 Lung Cancer 3.5 IPF 3.6 Pulmonary Vascular Diseases 4 Conclusions and Perspectives References WNT Signalling in Osteoarthritis and Its Pharmacological Targeting 1 Introduction 1.1 The Pathogenesis of Osteoarthritis 1.2 The WNT Signalling 1.3 The WNT/β-Catenin Signalling in OA 2 Modulation of the WNT/β-Catenin Signalling to Halt OA Progression 2.1 Extracellular Modulators 2.1.1 Soluble Inhibitors 2.1.2 WNT16 2.1.3 Receptor-Mediated Inhibition 2.2 Intracellular Modulation 2.2.1 XAV-939 2.2.2 β-Catenin 2.2.3 DOT1L 2.3 Cross-Talk Between β-Catenin Dependent and Independent Cascades 3 Lorecivivint 4 Conclusions References WNT Signaling Is a Key Player in Alzheimer´s Disease 1 WNT Signaling Pathway 2 WNT/β-Catenin Signaling Pathway 3 WNT/PCP Pathway 4 WNT/Ca2+ Pathway 5 WNT/Ror2 Signaling 6 WNT Signaling Function in the Adult Central Nervous System (CNS) 7 WNT Signaling and AD 8 WNT Signaling Loss Promotes the Appearance of AD 9 Link between WNT Signaling and Glucose Metabolism 10 Inflammatory Axis and WNT Signaling 11 Overview of Inflammation in AD 12 The Inflammatory Cascade and the WNT Signaling Crosstalk 13 Concluding Remarks References Pharmacologically Targeting the WNT/β-Catenin Signaling Cascade: Avoiding the Sword of Damocles 1 Introduction 2 The WNT/β-Catenin Signaling Pathway and What Makes It So Difficult to Target Safely 3 Nonspecific WNT/β-Catenin Signaling Pathway Modulators 4 Molecularly Targeted Agents 4.1 β-Catenin-TCF Inhibitors 4.2 PDZ Domain of DVL Binders 4.3 Porcupine and Tankyrase Inhibitors 4.4 Other Enzyme Inhibitors 4.5 Biological Agents 4.6 Small-Molecule Antagonists of FZD 4.7 WNT Co-activator Modulators 5 From Bench to Bedside 6 Lessons Learned to Date 7 Why CBP/β-Catenin Antagonists Are Safe 8 Conclusion References