Drug Design and Discovery: Inhibitors of Mitogen-Activated Protein Kinases

This book covers the important role small molecules can play in the modulation of stress-activated protein kinase (SAPK), also called the mitogen-activated protein kinase (MAPK) pathway, and the potential this may offer in enabling the development of future medicine therapies. It is clear that MAP kinase pathway therapies could continue to drive increasing interest in the field, both within academic laboratories and also in the biotechnology and pharmaceutical sectors. This book provides an overview of protein kinase inhibitors, the biological roles of MAP kinases, ATP-competitive and non-competitive inhibitors, covalent inhibitors, and more. This book is intended for professors in academia, researchers in pharmaceutical and biotechnology sectors working on protein kinases, and graduate students in pharmacy/chemistry. Cover Half Title Drug Design and Discovery: Inhibitors of Mitogen-Activated Protein Kinases Copyright Preface Contents About the Author Common Abbreviations and Acronyms 1. An Overview of Protein Kinase Inhibitors 1.1 Introduction 1.1.1 Classification of Kinases 1.1.2 Protein Kinase Domains 1.1.3 Types of Kinase Inhibitors 1.1.4 FDA-Approved Kinase Inhibitors 1.1.5 Chemical Structure of FDA-Approved Kinase Inhibitors 1.1.6 MAP Kinases 1.1.6.1 Extracellular Signal-Regulated Kinases (ERKs) 1.1.6.2 c-Jun N-terminal Kinases (JNKs) 1.1.6.3 p-38 MAK Kinases 1.1.6.4 Nemo-Like Kinase (NLK) 1.1.6.5 MAP Kinase Family References 2. Biological Roles of MAP Kinases 2.1 Introduction 2.2 MAPK Pathway: The Basics 2.3 Role of MAP Kinases 8, 9, 10 in Neurodegenerative Diseases 2.4 Role of MAP Kinases 8, 9, 10 in Obesity and Type-2 Diabetes 2.5 Role of MAP Kinases 8, 9, 10 in Rheumatoid Arthritis 2.6 Role of MAP Kinases 8, 9, 10 in Bronchial Asthma 2.7 Role of MAP Kinases 8, 9, 10 in Oncology 2.8 Structures of MAPK 8, 9, 10 2.9 Interactions of MAPK8, 9, 10 with Other Proteins 2.10 Localization of MAP Kinases 2.11 Landmark of MAP Kinases 8, 9, 10 References 3. ATP-Competitive Inhibitors of MAP Kinases 3.1 Introduction 3.2 ATP-Competitive Inhibitors of JNK 3.2.1 Inhibitors from Serono 3.3 Inhibitors from Eisai 3.4 Inhibitors from Pfizer 3.5 Inhibitors from Abbott Lab 3.6 Inhibitors from Elan Pharmaceuticals 3.7 Inhibitors from Roche 3.8 Inhibitors from Takeda 3.9 Inhibitors from AstraZeneca 3.10 Inhibitors from Vertex 3.11 Inhibitors from GSK 3.12 Inhibitors from Union Chimique Belge (UCB) 3.13 Inhibitors from Universität Tübingen 3.14 Inhibitors from Scripps Research Institute 3.15 Inhibitors from Hanyang University 3.16 Inhibitors from Celgene (Now BMS) 3.17 Inhibitors from CHDI Foundation 3.18 Inhibitors from Peking University 3.19 Inhibitors from Montana State University 3.20 Inhibitors from Nanjing Tech University 3.21 Inhibitors from Sichuan University 3.22 Development of New Clinical Candidate CC-90001 as a JNK Inhibitor 3.23 ATP-Competitive ERK1/2 Inhibitors 3.24 Development of Clinical Candidates as ERK1/2 Inhibitors 3.25 Development of Clinical Candidates as p38 MAPK Inhibitors References 4. Non-ATP Site Inhibitors and Bi-dentate Inhibitors 4.1 Introduction 4.2 Small Peptides as ATP-Noncompetitive Inhibitors of MAPK 8, 9, 10 4.3 Small Molecules as ATP-Noncompetitive JNK (MAPK 8, 9, 10) Inhibitors 4.4 Dual Site Binding MAP Kinase 8, 9, 10 Inhibitors 4.5 Bi-dentate Inhibitors of MAP Kinase 8, 9, 10 4.6 Small Molecule Bi-dentate Inhibitors of MAK Kinase 8, 9, 10 4.7 Allosteric Inhibitors of ERK1/2 (Non-ATP-Competitive ERK Inhibitors) 4.8 Allosteric Inhibitors of p38 MAPK 4.9 Development of Clinical Candidate BIRB-796 as an Allosteric p38 MAP Kinase Inhibitor References 5. Covalent Inhibitors of MAP Kinases 5.1 Introduction 5.2 Ritlecitinib 5.3 Dimethyl Fumarate 5.4 Wortmannin 5.5 Afatinib 5.6 Ibrutinib 5.7 Bortezomib 5.8 Irreversible Covalent Inhibitors 5.9 Reversible Covalent Inhibitors 5.10 Irreversible Covalent Binding Warheads 5.11 Reversible Covalent Binding Warheads 5.12 Representative Targeted Covalent Inhibitors and Their Target and Indication 5.13 Covalent Inhibitors of MAPK 8, 9, 10 (JNKs) 5.13.1 Covalent Inhibitors of ERK1, 2 5.13.2 Fragment-Based Discovery of Covalent ERK1/2 Inhibitor 5.13.3 Covalent ERK1/2 Inhibitor Targeting Outside of ATP Binding Site 5.13.3.1 Development of Covalent Clinical Candidate CC-90003 as ERK1/2 Inhibitor 5.14 Covalent Inhibitors of p38 MAP Kinases References Index