János Fischer, PhD, is a Senior Research Scientist at Richter Plc., Budapest, Hungary, and is Member of the Subcommittee on Drug Discovery and Development of IUPAC. Christian Klein, PhD, is Department Head Cancer Immunotherapy Discovery 3 and Site Head at the Roche Innovation Center Zurich, specialized in the discovery, validation, and preclinical development of antibody based cancer immunotherapies and bispecific antibodies. Wayne E. Childers, PhD, is Associate Professor of Pharmaceutical Sciences at Temple University School of Pharmacy, Philadelphia, USA.

• Advisory Board Members xiPreface xiiiPart I General Aspects 11 Drug Discovery in Academia 3Oliver Plettenburg1.1 Introduction 31.2 Repurposing Drugs 51.2.1 Thalidomide Derivatives 51.2.2 Chemotherapy: Nitrogen Mustards 61.3 Pregabalin 81.4 Natural Product-Derived Drug Discovery 101.4.1 Antibiotics 111.4.2 Anticancer Drugs 121.4.2.1 Camptothecin 121.4.2.2 Taxol 141.4.2.3 Epothilones 171.4.2.4 Eribulin 181.4.3 Artemisinin and Artemether 201.4.4 Carfilzomib 211.5 Biologic Drugs 231.5.1 Insulin 231.5.2 Rituximab 251.5.3 Alglucerase 261.6 Conceptionally New Small Molecule Drugs 271.6.1 Histone Deacetylase Inhibitors 271.6.2 Acyclic Nucleoside Phosphonates 291.6.3 Darunavir 311.6.4 Sunitinib 321.7 Sweet Spot for Academic Drug Discovery 34List of Abbreviations 36References 37Biography 462 From Degraders to Molecular Glues: New Ways of Breaking Down Disease-Associated Proteins 47Yvonne A. Nagel, Adrian Britschgi and Antonio Ricci2.1 Introduction 472.2 Definition and Historical Development of Degraders 472.3 The Ubiquitin–Proteasome System and Considerations of E3 Ligases 532.4 General Design Aspects 552.5 Differentiation of the Degrader Technology to Traditional Approaches 582.5.1 The Ability to Expand the Druggable Proteome 582.5.2 Overcoming the Accumulation of Target Protein 592.5.3 Abrogating Scaffolding Functions 592.5.4 Creating Target Specificity 602.5.5 Catalytic Mode of Action 602.5.6 Event-Driven Pharmacology and Prolonged PD Effect 612.6 Potential Disadvantages and Limitations of Degraders 622.7 Molecular Glue-like Degraders and Monovalent Degraders 642.7.1 Definitions and Historical Perspective 642.7.2 State of the Art 672.8 Future Directions (Status Q3 2020) 702.9 Summary and Conclusions 71Acknowledgments 71List of Abbreviations 72References 73Biographies 84Part II Drug Class Studies 873 GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes and Obesity 89Lars Linderoth, Jacob Kofoed, János T. Kodra, Steffen Reedtz-Runge and Thomas Kruse3.1 Introduction 893.2 GLP-1 Biology 903.2.1 GLP-1 Receptor Binding and Activation 913.2.2 GLP-1 Pharmaceutical Developments 923.3 Ex4-Based Analogues 923.3.1 Exenatide 923.3.2 Exenatide LAR 943.3.3 Lixisenatide 943.3.4 Efpeglenatide 943.3.5 Pegylated Loxenatide 953.4 GLP-1 Based Analogues 953.4.1 Liraglutide 953.4.2 Semaglutide 963.4.3 Taspoglutide 973.4.4 Albiglutide and Albenatide 983.4.5 Dulaglutide 983.5 Co-agonists 993.5.1 GLP-1/GIP Co-agonists 1003.5.2 GLP-1/Glucagon Co-agonists 1003.5.2.1 Other GLP-1R Agonists 1003.6 Summary 102List of Abbreviations 103References 104Biographies 1084 Recent Advances on SGLT2 Inhibitors: Synthetic Approaches, Therapeutic Benefits, and Adverse Events 111Ana M. de Matos, Patrícia Calado, William Washburn and Amélia P. Rauter4.1 Introduction 1114.2 The Mechanism of Action of SGLT2 Inhibitors 1124.3 Synthetic Approaches to Gliflozins 1134.3.1 Dapagliflozin 1144.3.2 Sotagliflozin 1194.3.3 Empagliflozin 1194.3.4 Bexagliflozin 1224.3.5 Luseogliflozin 1234.3.6 Tofogliflozin 1254.3.7 Ertugliflozin 1284.3.8 Ipragliflozin 1294.3.9 Canagliflozin 1304.3.10 Remogliflozin 1334.4 Clinical Benefits of SGLT2 Inhibitors 1344.4.1 Reduction in HbA1C Levels 1344.4.2 Protection Against Cardiovascular Events in Diabetic Patients 1374.4.3 Renoprotection in Patients with T2D 1394.4.4 Bodyweight Reduction 1404.5 Safety Profile and Particularly Relevant Adverse Events Associated with SGLT2 Inhibitors 1414.6 Application of SGLT2 Inhibitors in Type 1 Diabetes 1434.7 Conclusions 145Acknowledgments 146List of Abbreviations 146References 148Biographies 1555 CAR T Cells: A Novel Biological Drug Class 159Whitney Gladney, Julie Jadlowsky, Megan M. Davis and Andrew Fesnak5.1 Introduction 1595.2 A Brief History of Cell-Based Therapies 1595.3 Genetically Engineered T Cell Therapy Products 1625.3.1 T Cell Receptor-Engineered T Cells 1625.3.1.1 Intro to TCRs 1625.3.1.2 Challenges with TCR-Engineered T Cells 1655.3.2 CAR T Cells 1655.3.2.1 What Is a CAR? 1655.3.2.2 Why Do You Put a CAR into a T Cell (as Opposed to Another Cell)? 1675.4 CAR T Cells: The Living Drug 1695.4.1 Early Signals of CAR T Cell Efficacy 1695.4.2 CART19 Pharmacokinetics 1705.4.2.1 Expansion 1705.4.2.2 Persistence 1715.4.2.3 Trafficking 1725.4.3 Biomarkers of CAR T Cell Quality 1725.4.4 Side Effects of CAR T Cell Therapy 1735.4.4.1 Cytokine Release Syndrome 1735.4.4.2 CAR T Cell Associated Neurotoxicity 1745.4.4.3 On-Target, Off-Tumor Toxicities 1755.4.5 Challenges Encountered with Therapeutic Application of CAR T Cells 1765.4.5.1 Production Issues 1765.4.5.2 Therapeutic Resistance 1795.5 Translation from Laboratory Innovation to Approved Therapy 1835.6 Future Directions and CAR T Programs to Consider 1865.6.1 Approved Therapies 1865.6.2 Pre-registration Therapies 1875.7 Additional Resources for Supplementary Information on Cellular Therapies, Including Regulations, Notifications, and Guidelines 188List of Abbreviations 190References 192Biographies 1976 CGRP Inhibitors for the Treatment of Migraine 199Sarah Walter and Marcelo E. Bigal6.1 Introduction 1996.2 The Overall Physiological Role of CGRP 2006.3 The Role of CGRP in the Gut 2036.4 What Is the Role of CGRP in Migraine? 2036.4.1 Small-Molecule Antagonists 2046.4.2 Large-Molecule Antagonists 2086.5 Role of CGRP Antagonists in Other Indications 2116.6 Conclusions 212List of Abbreviations 212References 213Biographies 219Part III Case Studies 2217 Discovery and Development of Emicizumab (HEMLIBRA®): A Humanized Bispecific Antibody to Coagulation Factors IXa and X with a Factor VIII Cofactor Activity 223Takehisa Kitazawa, Koichiro Yoneyama and Tomoyuki Igawa7.1 Introduction 2237.2 Preclinical Experience with Emicizumab 2257.2.1 Brief History on Discovery of Emicizumab 2257.2.1.1 Idea Inspiration of an Asymmetric Bispecific IgG Antibody to FIXa and FX with FVIII-Cofactor Function 2257.2.1.2 From the First Immunization to the Identification of the Clinical Candidate (ACE910 = Emicizumab) 2267.2.2 Mechanism of Action and Nonclinical Characteristics of Emicizumab 2297.2.2.1 Mechanism of Action and In Vitro Characteristics of Emicizumab 2297.2.2.2 In Vivo Characteristics of Emicizumab 2307.2.3 Molecular Engineering Technologies Incorporated in Emicizumab for Industrial Manufacturing 2317.2.3.1 Obtaining a Common Light Chain 2327.2.3.2 Separation and Purification from By-products 2327.2.3.3 Minimizing the Amount of Homodimeric By-products 2337.2.3.4 Application of Technology 2337.2.4 Conclusions from Preclinical Studies 2337.3 Clinical Experience with Emicizumab 2347.3.1 Early-Phase Clinical Development 2357.3.1.1 Phase I and I/II Studies 2357.3.1.2 Clinical Pharmacology Investigations 2377.3.2 Late-Phase Clinical Development 2397.3.2.1 Non-interventional Study 2397.3.2.2 Phase III Studies with Once-Weekly Dosing in Patients with FVIII Inhibitors 2397.3.2.3 Phase III Studies with Once-Weekly, Every-2-Week, or Every-4-Week Dosing in Patients with or without FVIII Inhibitors 2407.4 Conclusions 242Acknowledgments 242Conflict of Interests 242List of Abbreviations 243References 243Biographies 2478 Discovery and Development of Ivosidenib (AG-120: TIBSOVO®) 249Zenon D. Konteatis and Zhihua Sui8.1 Introduction 2498.2 Crystal Structure of IDH1 2508.3 Search for mIDH1 Inhibitors 2508.4 Hit to Lead Exploration 2528.5 Lead Optimization: Discovery of AG-120 2578.6 Synthesis of AG-120 2608.7 Preclinical Characterization of AG-120 2618.8 Ivosidenib Clinical Studies 2628.9 Conclusions 267List of Abbreviations 268References 268Biographies 2709 The Discovery of Kisqali®(Ribociclib): A CDK4/6 Inhibitor for the Treatment of HR+/HER2− Advanced Breast Cancer 273Christopher T. Brain, Rajiv Chopra, Sunkyu Kim, Steven Howard and Moo Je Sung9.1 Disease Background 2739.2 Target Background and Validation: The Cell Cycle 2749.3 Commencement of Drug Discovery Efforts 2769.4 Fragment-based Approach 2769.5 Cross-Screening of Existing Kinase Assets Leading to Ribociclib 2779.6 Combination Treatments with Ribociclib 2829.7 Early-Phase Clinical Studies 2839.8 Phase 3 Clinical Studies 2849.9 Conclusions 285Acknowledgments 285List of Abbreviations 285References 286Biographies 288Index 291

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