in Other Indications
6.6 Conclusions
List of Abbreviations
References
Biographies
8 Part III: Case Studies 7 Discovery and Development of Emicizumab (HEMLIBRA® ): A Humanized Bispecific Antibody to Coagulation Factors IXa and X with a Factor VIII Cofactor Activity 7.1 Introduction 7.2 Preclinical Experience with Emicizumab 7.3 Clinical Experience with Emicizumab 7.4 Conclusions Acknowledgments Conflict of Interests References Biographies 8 Discovery and Development of Ivosidenib (AG‐120: TIBSOVO® ) 8.1 Introduction 8.2 Crystal Structure of IDH1 8.3 Search for mIDH1 Inhibitors 8.4 Hit to Lead Exploration 8.5 Lead Optimization: Discovery of AG‐120 8.6 Synthesis of AG‐120 8.7 Preclinical Characterization of AG‐120 8.8 Ivosidenib Clinical Studies 8.9 Conclusions References Biographies 9 The Discovery of Kisqali® (Ribociclib): A CDK4/6 Inhibitor for the Treatment of HR+/HER2− Advanced Breast Cancer 9.1 Disease Background 9.2 Target Background and Validation: The Cell Cycle 9.3 Commencement of Drug Discovery Efforts 9.4 Fragment‐based Approach 9.5 Cross‐Screening of Existing Kinase Assets Leading to Ribociclib 9.6 Combination Treatments with Ribociclib 9.7 Early‐Phase Clinical Studies 9.8 Phase 3 Clinical Studies 9.9 Conclusions Acknowledgments References Biographies
9 Index
List of Tables
1 Chapter 2Table 2.1 Selected examples of different target types that have been successf...
2 Chapter 4Table 4.1 Summary of the first results of randomized controlled trials testin...
3 Chapter 5Table 5.1 Ongoing CAR T cell clinical trials.
4 Chapter 6Table 6.1 Summary of CGRP/CGRP‐R mABs.
5 Chapter 7Table 7.1 Annualized bleeding rates for bleeding events treated with coagulat...
6 Chapter 8Table 8.1 R1 Initial SAR based on the enzymatic activity of derivatives of 2,Table 8.2 R2 Initial SAR based on the enzymatic activity of derivatives of N‐...Table 8.3 R3 initial SAR based on the enzymatic activity of the phenyl‐glycin...Table 8.4 R4 Initial SAR based on the enzymatic activity of derivatives of 2,Table 8.5 Cell potency of selected potentN‐phenyl glycine analogues.Table 8.6 Second round SAR optimization: enzymatic activity, cellular potency...Table 8.7 Reduction of hPXR activation leading to AG‐120.Table 8.8 Biochemical and Cellular Profiling ofAG‐120.Table 8.9In vitro ADME and in vivo PK properties of AG‐120.
List of Illustrations
1 Chapter 1Figure 1.1 FDA drug approvals from 1990 to 2019.Figure 1.2 S‐Lost, N‐Lost, modern agents.Figure 1.3 GABA biology.Figure 1.4 3‐Me‐GABA analogues synthesized by Andruskiewicz and Silverman.Figure 1.5 Lead structures isolated from natural sources.Figure 1.6 Camptothecin and approved derivatives.Figure 1.7 Taxol derivatives.Figure 1.8 Semisynthetic approaches to Taxol.Figure 1.9 Epothilone derivatives.Figure 1.10 Structures of halichondrin B, eribulin mesylate, and E7130.Figure 1.11 Seeberger's flow synthesis of artemisinin and artemether, essent...Figure 1.12 Epoxomicin binding to the 20S‐ribosome.Figure 1.13 From epoxomicin to carfilzomib.Figure 1.14 Structures of DMSO and hydroxamic acid derivatives leading to th...Figure 1.15 Structures of antiviral compounds developed by Hóly and De Clerc...Figure 1.16 HIV protease
