Lead Generation

In this comprehensive two-volume resource on the topic senior lead generation medicinal chemists present a coherent view of the current methods and strategies in industrial and academic lead generation. This is the first book to combine both standard and innovative approaches in comparable breadth and depth, including several recent successful lead generation case studies published here for the first time. Beginning with a general discussion of the underlying principles and strategies, individual lead generation approaches are described in detail, highlighting their strengths and weaknesses, along with all relevant bordering disciplines like e.g. target identification and validation, predictive methods, molecular recognition or lead quality matrices. Novel lead generation approaches for challenging targets like DNA-encoded library screening or chemical biology approaches are treated here side by side with established methods as high throughput and affinity screening, knowledge- or fragment-based lead generation, and collaborative approaches. Within the entire book, a very strong focus is given to highlight the application of the presented methods, so that the reader will be able to learn from real life examples. The final part of the book presents several lead generation case studies taken from different therapeutic fields, including diabetes, cardiovascular and respiratory diseases, neuroscience, infection and tropical diseases. The result is a prime knowledge resource for medicinal chemists and for every scientist involved in lead generation.

Auteur
Joerg Holenz is a trained organic and medicinal chemist and acquired his PhD in Germany on the synthesis of alkaloids as antimalarial agents. After leading the preclinical activities of the marketed analgesic Tapentadol (Grunenthal Pharmaceuticals GmbH), he headed the medicinal chemistry department of Barcelona-based Laboratorios Esteve. He then moved to AstraZeneca's CNS/ pain research unit in Sweden to head lead generation chemistry. In 2012, Joerg was selected to join AZ's newly formed 'virtual' neuroscience unit in Boston as director of discovery and preclinical sciences. As a project leader he is responsible for pioneering a novel concept of driving research and development projects via increased use of academic and industry collaborative networks. In his career, Joerg worked predominantly with peripheral and central targets in the pain and neuroscience disease areas. He has edited, authored or contributed to more than 45 publications, 50 patent applications and several books and book chapters.

Contenu

Dedication V

List of Contributors XXI

Preface XXVII

A Personal Foreword XXXI

Volume 68a

Part I Introduction to Lead Generation 1

1 Introduction: Learnings from the Past Characteristics of Successful Leads 3
Mike Hann

Acknowledgments 10

References 10

2 Modern Lead Generation Strategies 13
Jörg Holenz and Dean G. Brown

2.1 Lead Generation Greatly Influences Clinical Candidate Quality 14

2.2 Screening of Compound Libraries has Undergone a Major Paradigm Change 15

2.3 New Chemical Modalities are Available to Tackle Difficult Targets 15

2.4 As Demands have Increased, New Lead Generation Methods Emerged 16

2.5 How do Lead Generation Chemists Meet These Challenges and Subsequently Provide Their Lead Optimization Colleagues with High-Quality Lead Series? 17

2.5.1 Learnings can be Drawn from LG Project Failures 17

2.5.2 How Many Compounds to Screen to Generate High-Quality Leads? 18

2.5.3 Which Compounds to Screen to Generate High-Quality Leads? 19

2.5.4 Developing Project-Customized, Concerted, and Comprehensive Lead Generation Strategies will Increase LG Success Rates: the CREATION of Leads 20

2.5.5 Selecting the Target Defines LG Success Rates 21

2.5.6 Lead Generation should be Complemented by Auxiliary Technologies to Characterize Hits 21

2.5.7 Phenotypic Screens are Often Complemented by a Chemical Biology Arm 22

2.5.8 The Lead Generation Strategy is Defined by the Budget Allocated 22

2.5.9 Cost-Efficient but Information-Rich Lead Generation Strategies 23

2.5.10 The Revival of Potency as the Most Important Lead Criterion? 24

2.5.11 When has a LG Campaign Delivered Successfully? 27

References 31

Part II The Importance of Target Identification for Generating Successful Leads 35

3 Ligandability of Drug Targets: Assessment of Chemical Tractability via Experimental and In Silico Approaches 37
Udo Bauer and Alexander L. Breeze

3.1 Introduction 37

3.2 The Concept of Ligandability 39

3.2.1 General Characteristics of Ligandable Targets 39

3.3 The Intersection of Ligandability and Human Disease Target Space 40

3.3.1 Experimental Techniques for Assessing Target Ligandability 42

3.3.1.1 High-Throughput Screening and Subset/Validation Set Screening 43

3.3.1.2 Fragment Screening 44

3.4 Practical Examples of the Use of Fragment Screening for Ligandability Assessment 50

3.4.1 Chemical Tractability Assessment by in silico Approaches 54

3.4.1.1 Pocket-Finding Algorithms 54

3.4.1.2 Discrimination Functions and Validation Sets 55

3.4.1.3 Simulation-Based Methods for Identifying Interaction Potentials 56

3.5 Conclusions and Outlook 56

References 58

4 Chemistry-Driven Target Identification 63
Iván Cornella-Taracido, Ryan Hicks, Ola Engkvist, Adam Hendricks, Ronald Tomlinson, and M. Paola Castaldi

4.1 Introduction 63

4.2 Chemistry-Driven Target Discovery: Enabling Biology 65

4.2.1 Biological Samples 65

4.2.2 Cells Cultured in 2D 66

4.2.3 Cells Cultured in 3D, Organoids, and Tissues 67

4.2.4 Nonhuman Cells and Whole-Organism Screening 68

4.2.5 Functional Assays and Readouts 68

4.3 Chemistry for Target Discovery 71

4.3.1 Screening Deck Selection 71

4.3.2 Triaging and Prioritization of Chemical Matter 72

4.3.3 SAR Expansion and Probe Synthesis for Target Deconvolution 73

4.4 Small-Molecule Target Identification Techniques 75

4.4.1 In Silico Target Deconvolution 75

4.4.2 Biochemical Profiling 77

4.4.3 Target Deconvolution Correlational Tools 78

4.4.4 Subcellular Localization 79

4.4.5 Chemical Genetics 79

4.4.6 Affinity Chemical Proteomics 81

4.4.7 Target Corroboration 84 4.5 Conclusions 86</p&gt...