Foreword xiii Preface xv Acknowledgments xix Epigraph xxi 1 The History of Molecular Medicine 1 1.1 Disease and Treatments in Antiquity 2 1.2 Natural Products as Medicines 2 1.3 Isolation of Active Ingredients and Chemical Synthesis 4 1.4 The Receptor Theory of Drug Action 9 1.5 Early Chemotherapy: Attempts to Mimic Nature 15 1.6 Linus Pauling Establishes Sickle Cell Anemia as a Molecular Disease 19 1.7 ACE Inhibitors: An Early Example of Targeted Therapeutics 21 1.

8 Genetic Alterations in Disease 26 1.9 Structure-Based Drug Design 28 1.10 Recombinant DNA and Protein Engineering 31 1.11 Modern Drug Discovery 35 1.12 Summary 38 2 Molecular Targeted Therapeutic Modalities 45 2.1 Candidate Drug Profile 48 2.2 Biologic Therapeutics 49 2.3 Small-Molecule Drugs 55 2.

4 Antibody-Drug Conjugates (ADCs) 98 2.5 Summary 100 3 Target Selection 107 3.1 Disease Relevance 108 3.2 Selective Essentiality and Therapeutic Index 122 3.3 Actionability 132 3.4 Unmet Medical Need 138 3.5 DHX9: An Illustrative Example of Target Validation 140 3.6 Summary 145 4 Hit-Finding and Hit-Validation 151 4.

1 Properties of Small-Molecule Therapeutics 152 4.2 Hit-Validation Criteria 153 4.3 Screening Strategies 155 4.4 Protein Constructs for Screening 156 4.5 Compound Sources for Screening 158 4.6 Assay Formats 169 4.7 Measures of Assay Performance 178 4.8 Orthogonal Assays and Mode of Modulation 186 4.

9 Confirmation of Chemical Purity and Identity 188 4.10 Hit Expansion 188 4.11 Hit-Validation Funnel 189 4.12 Summary 191 5 FromHitstoLeads197 5.1 The Project Matrix Team 198 5.2 Target Potency and Selectivity 200 5.3 Cellular Assays 212 5.4 ADME Properties 225 5.

5 Chemical Tractability 232 5.6 Lead Series 234 5.7 Case Studies 240 5.8 Summary 247 6 Lead Optimization 251 6.1 Typical Criteria for Development Candidate Declaration 252 6.2 Continued Optimization of Target Potency, Selectivity, and Cellular Potency 252 6.3 In Vitro ADME Properties 271 6.4 In Vivo ADME Properties 280 6.

5 In Vivo Drug Efficacy 289 6.6 Allometric Scaling and Predicted Human Dose 309 6.7 Preliminary Safety Assessment in Two Species 312 6.8 Summary 313 Appendix 1 Kinetic and Equilibrium Assessment of Receptor-Ligand Interactions 319 A1.1 The Equilibrium Dissociation Constant, Kd 320 A1.2 The Kinetics of Approach to Equilibrium 321 A1.3 Kinetics of Irreversible or Pseudo-Irreversible Processes 323 A1.4 Binding Measurements at Equilibrium 324 A1.

5 Extension to Other Pharmacological Situations 327 Appendix 2 Investigational New Drug (IND) Applications 331 A2.1 Types of IND Applications 332 A2.2 Key Content of an IND Application 333 A2.3 Review by FDA 334 A2.4 IND-Enabling Studies 335 References 340 Index 341.