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Abstract
Kinase inhibition remains an area of significant interest, and growing importance, across academia and the pharmaceutical industry. There are now many marketed drugs that target kinases and a significant number of compounds are currently in various stages of clinical development. This book is a forward-looking analysis of a number of key areas for kinase inhibition in the coming years and builds on the first volume. This includes topics such as screening approaches to target kinases along with different modes of inhibition such as allosteric and covalent. Novel approaches such as macrocyclisation are considered along with how the properties of kinase inhibitors have evolved, including the potential for brain penetration. Recent areas of great importance also covered include cutting edge molecular modelling approaches and the importance of kinase mutations. The evolving biology of kinases has also resulted in increased interest in the immuno-oncology area and also pseudokinases as a target family. As with the first volume the book finishes with a forward looking view of how research against this fascinating target class may evolve.
Dr Frederick W Goldberg is a Medicinal Chemist at AstraZeneca, UK. He received his MSci at Cambridge University, PhD at Imperial College London and a Postdoc (Fulbright scholarship) at the University of Texas at Austin. He has extensive experience of leading both chemistry and project teams within oncology, including targets that have delivered clinical candidates. He has over 30 published papers and patents, including a number of research papers and perspective articles on kinases. Dr Richard A Ward is a Computational Medicinal Chemist at AstraZeneca, UK. He received his BSc (Hons) in Chemistry with Bio-organic Chemistry at The University of Birmingham and gained a PhD in Computational Chemistry also at The University of Birmingham, under the supervision of Dr John Wilkie. He has extensive experience in target selection, lead generation and lead optimisation against kinase and non-kinase targets with a specialisation in covalent drug discovery. Along with publishing a number of papers on kinases, Richard is a co-inventor of the EGFR mutant kinase inhibitor osimertinib.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Kinase Drug Discovery: Modern Approaches | i | ||
| About the Editors | vii | ||
| Contents | ix | ||
| Chapter 1 - Introduction to Kinase Drug Discovery – Modern Approaches | 1 | ||
| 1.1 Kinase Drug Discovery | 1 | ||
| 1.2 Preview of Topics Covered | 4 | ||
| 1.3 Conclusions | 7 | ||
| Acknowledgements | 8 | ||
| Reference | 8 | ||
| Chapter 2 - New Screening Approaches for Kinases | 9 | ||
| 2.1 Introduction | 9 | ||
| 2.2 Fragment Screening | 10 | ||
| 2.3 DNA-encoded Library Screening for Kinases | 13 | ||
| 2.3.1 DEL Screening as a Complementary Approach | 15 | ||
| 2.3.2 DEL Derived Clinical Candidate | 16 | ||
| 2.3.3 DEL Future Directions | 17 | ||
| 2.4 Thermal Shift Screening by Differential Scanning Fluorimetry (DSF) | 18 | ||
| 2.4.1 DSF Future Directions | 19 | ||
| 2.5 Cellular Kinase Screens | 19 | ||
| 2.5.1 Immunocytochemical Assays | 20 | ||
| 2.5.2 Ba/F3 Cellular Assays | 20 | ||
| 2.5.3 Selected Examples of Kinase Phenotypic Screening | 21 | ||
| 2.5.4 Cellular Kinase Screens Future Directions | 23 | ||
| 2.6 Chemical Proteomics | 23 | ||
| 2.6.1 Kinase Affinity Resins | 23 | ||
| 2.6.2 Affinity Based Protein Profiling (ABPP) | 24 | ||
| 2.6.3 Higher-throughput Chemical Proteomics | 25 | ||
| 2.6.4 Future Directions | 26 | ||
| 2.7 Summary and Conclusions | 26 | ||
| References | 27 | ||
| Chapter 3 - The Screening and Design of Allosteric Kinase Inhibitors | 34 | ||
| 3.1 Introduction | 34 | ||
| 3.2 Serendipitous Discovery of Allosteric Small Molecule Inhibitors | 37 | ||
| 3.2.1 Biochemical-based HTS Assays | 37 | ||
| 3.2.1.1 Akt Inhibitors | 37 | ||
| 3.2.1.2 LIMK2 Inhibitors | 38 | ||
| 3.2.1.3 IGF1R Inhibitors | 38 | ||
| 3.2.2 Cellular-based HTS Assays | 39 | ||
| 3.2.2.1 MAPK and MEK Inhibitors | 39 | ||
| 3.2.2.2 Bcr-Abl Inhibitors | 40 | ||
| 3.3 Rational Approaches Involving High-ATP Concentration Testing | 41 | ||
| 3.3.1 Secondary Screening Using High-ATP Concentration | 41 | ||
| 3.3.1.1 EGFR Inhibitors | 41 | ||
| 3.3.1.2 CHK1 Inhibitors | 42 | ||
| 3.3.1.3 PAK1 Inhibitor | 43 | ||
| 3.3.2 Hit Validation Using High-ATP Concentration Assays | 44 | ||
| 3.4 Other Specifically Designed Methods | 46 | ||
| 3.4.1 Fragment-based Screening | 46 | ||
| 3.4.1.1 Bcr-Abl Inhibitor | 46 | ||
| 3.4.1.2 PAK Inhibitors | 47 | ||
| 3.4.2 Screening Against Inactive Unphosphorylated Kinases | 48 | ||
| 3.4.2.1 FAK Inhibitors | 48 | ||
| 3.4.2.2 JNK Inhibitors | 49 | ||
| 3.4.2.3 p38α Inhibitor | 49 | ||
| 3.4.2.4 Akt1 Inhibitors | 51 | ||
| 3.4.3 Fluorescence-based Assays | 51 | ||
| 3.4.3.1 cSrc Inhibitors | 51 | ||
| 3.4.3.2 Allosteric AURKA Inhibitors Disrupting Protein–Protein Interaction | 52 | ||
| 3.5 Peptide-based Allosteric Inhibitors | 53 | ||
| 3.6 Conclusions | 54 | ||
| Acknowledgements | 55 | ||
| References | 56 | ||
| Chapter 4 - Covalent Inhibition of Kinases | 61 | ||
| 4.1 Covalent Kinase Inhibitors: General Considerations | 61 | ||
| 4.1.1 Drug-target Residence Time and Toxicity | 62 | ||
| 4.1.2 Inhibitor Selectivity | 62 | ||
| 4.1.3 Inhibition Kinetics of Covalent Inhibitors | 63 | ||
| 4.2 Covalent Irreversible Kinase Inhibitors | 65 | ||
| 4.2.1 Group 1B Cysteine Kinases | 65 | ||
| 4.2.2 Group 3A Cysteine Kinases | 67 | ||
| 4.2.3 Group 3C Cysteine Kinase: FLT3 | 67 | ||
| 4.2.4 Group 3F Cysteine Kinases | 68 | ||
| 4.2.4.1 Irreversible EGFR Inhibitors | 68 | ||
| 4.2.4.1.1\rAfatinib.Epidermal growth factor receptor (EGFR) is an important target for the treatment of NSCLC as activating EGFR mutations ... | 68 | ||
| 4.2.4.1.2\rWZ4002.The first disclosed T790M mutant selective inhibitor (WZ4002) was identified by screening a focused library of common kin... | 70 | ||
| 4.2.4.1.3\rOsimertinib.In parallel, at AstraZeneca, a scaffold also containing a pyrimidine core was exploited to covalently target Cys797 ... | 71 | ||
| 4.2.4.1.4\rNazartinib.Nazartinib is an EGFR T790M inhibitor that at the time of writing is in phase II studies for the treatment of EGFR T7... | 72 | ||
| 4.2.4.1.5\rPF-06747775.Pfizer has also developed an EGFR T790M mutant selective inhibitor, known as PF-06747775, which is currently in phas... | 73 | ||
| 4.2.4.2 Irreversible BTK Inhibitors | 75 | ||
| 4.2.5 Irreversible JAK3 Inhibitors | 77 | ||
| 4.3 Group 4 Kinases | 79 | ||
| 4.3.1 ERK1/2 | 79 | ||
| 4.3.2 TAK1 | 81 | ||
| 4.4 Reversible Covalent Kinase Inhibitors | 83 | ||
| 4.4.1 Reversible Covalent Inhibitors of RSK2 and MSK1 | 83 | ||
| 4.4.2 Reversible Covalent Inhibitors of BTK | 85 | ||
| 4.4.3 Reversible Covalent Inhibitors of FGFR | 87 | ||
| 4.4.4 Reversible Covalent Inhibitors of JAK3 | 89 | ||
| 4.5 Conclusions | 90 | ||
| References | 90 | ||
| Chapter 5 - Small Molecule Macrocyclic Kinase Inhibitors | 97 | ||
| 5.1 Introduction to Macrocyclic Kinase Inhibitors | 97 | ||
| 5.2 Published Macrocyclic Kinase Inhibitors | 101 | ||
| 5.3 Case Studies | 101 | ||
| 5.4 Synthetic Approaches to Ring-closure | 107 | ||
| 5.4.1 Introduction to Ring-closure | 107 | ||
| 5.4.2 Ring Closing Metathesis | 109 | ||
| 5.4.3 Amide Coupling | 110 | ||
| 5.4.4 Palladium-catalyzed Arylation | 110 | ||
| 5.4.5 Buchwald–Hartwig Amination | 111 | ||
| 5.4.6 Ether Formation via Mitsunobu Reaction | 112 | ||
| 5.5 Modelling, Design and Physical Properties of Macrocyclic Kinase Inhibitors | 112 | ||
| 5.5.1 Binding-site of Macrocyclic Kinase Inhibitors | 112 | ||
| 5.5.2 Physical Properties | 113 | ||
| 5.5.3 Macrocycle Conformational Aspects | 114 | ||
| 5.5.4 Structure-based Design of Macrocyclic Kinase Inhibitors | 116 | ||
| 5.6 Macrocyclic Inhibitors in Clinical Testing | 117 | ||
| 5.7 Conclusions | 120 | ||
| References | 121 | ||
| Chapter 6 - The Design of Brain Penetrant Kinase Inhibitors | 128 | ||
| 6.1 Introduction | 128 | ||
| 6.2 CNS Drug Design: Considerations and Strategies | 131 | ||
| 6.3 Small Molecule CNS Penetrant Kinase Inhibitors for the Treatment of Cancer | 138 | ||
| 6.3.1 Oncology Clinical Kinase Targets with Evidence of Specific Design for CNS Penetration | 140 | ||
| 6.3.1.1 ALK | 140 | ||
| 6.3.1.2 EGFR | 142 | ||
| 6.3.1.3 PI3K/mTOR | 144 | ||
| 6.3.1.4 PLK1 | 146 | ||
| 6.3.2 Oncology Clinical Kinases With CNS Efficacious Inhibitors but Without Evidence of Rational Design for CNS Permeability | 147 | ||
| 6.3.2.1 Abl/Src | 147 | ||
| 6.3.2.2 BTK | 148 | ||
| 6.3.2.3 CDK4/6 | 148 | ||
| 6.3.2.4 HER2 | 149 | ||
| 6.3.2.5 MEK | 150 | ||
| 6.4 Targeting Kinases for CNS Disorders | 151 | ||
| 6.4.1 Leucine-rich Repeat Kinase 2 (LRRK2) | 152 | ||
| 6.4.2 c-Jun N-terminal Kinase (JNK) | 153 | ||
| 6.4.3 Casein Kinase 1 (CK1) | 154 | ||
| 6.4.4 Mixed-lineage Kinase (MLK) | 155 | ||
| 6.4.5 Glycogen Synthase Kinase 3 (GSK3) | 156 | ||
| 6.4.6 Dual Leucine Zipper Kinase (DLK) | 157 | ||
| 6.4.7 Bruton's Tyrosine Kinase (BTK) | 158 | ||
| 6.5 Summary and Future Perspectives | 159 | ||
| References | 160 | ||
| Chapter 7 - Cutting Edge Approaches to Structure-based Computational Modelling of Kinases | 181 | ||
| 7.1 Introduction | 181 | ||
| 7.1.1 Structural Data | 182 | ||
| 7.1.2 Type I Inhibitors | 184 | ||
| 7.1.3 Alternative Classes of Kinase Inhibitors | 185 | ||
| 7.1.4 Covalent Inhibition | 186 | ||
| 7.1.5 Thermodynamic Breakdown of the Steps in Ligand Binding | 186 | ||
| 7.2 Rigid-receptor Docking | 187 | ||
| 7.3 Rescoring Docked Poses with MM/GBSA | 190 | ||
| 7.4 Incorporating Protein Flexibility and Solvent Interactions into Docking Algorithms | 191 | ||
| 7.5 Understanding the Role of Solvent | 194 | ||
| 7.5.1 Using Water Analysis Approaches to Design Kinase Inhibitors | 194 | ||
| 7.5.2 Optimizing Binding Using WaterMap | 195 | ||
| 7.5.3 Optimizing Selectivity Using WaterMap | 195 | ||
| 7.6 Incorporating Water Interactions into Docking | 196 | ||
| 7.7 Free Energy Calculations | 198 | ||
| 7.8 Promising Computational Approaches Incorporating Dynamics | 203 | ||
| 7.8.1 Activation Mechanism | 203 | ||
| 7.8.2 Ligand Binding | 204 | ||
| 7.8.3 Ligand Selectivity | 206 | ||
| 7.8.4 Assessing Druggability of Kinases | 207 | ||
| 7.9 Conclusions | 208 | ||
| Acknowledgements | 209 | ||
| References | 209 | ||
| Chapter 8 - The Properties of Kinase Inhibitors | 216 | ||
| 8.1 Introduction | 216 | ||
| 8.2 Binding Pocket Properties by Structural Data | 218 | ||
| 8.2.1 Type I Inhibitors | 218 | ||
| 8.2.2 Type II Inhibitors | 220 | ||
| 8.2.3 Type III Inhibitors | 221 | ||
| 8.2.4 Type IV Inhibitors | 222 | ||
| 8.2.5 Type V Inhibitors | 224 | ||
| 8.2.6 Type VI: Irreversible Inhibitors | 224 | ||
| 8.3 Kinase Inhibitor Properties by Sets | 225 | ||
| 8.3.1 Physicochemical Property Analysis | 226 | ||
| 8.3.1.1 Molecular Weight | 226 | ||
| 8.3.1.2 clogP | 227 | ||
| 8.3.1.3 clogD | 228 | ||
| 8.3.1.4 Polar Surface Area | 229 | ||
| 8.3.1.5 Fraction sp3 | 230 | ||
| 8.3.2 ADME Property Analysis | 231 | ||
| 8.4 Conclusions | 233 | ||
| Acknowledgements | 234 | ||
| References | 234 | ||
| Chapter 9 - Assessment and Optimisation of Kinase Inhibitor Selectivity to Achieve Candidates with an Appropriate Safety Profile | 237 | ||
| 9.1 Introduction | 237 | ||
| 9.2 Type of Kinase Inhibition and Their Selectivity | 239 | ||
| 9.3 Pan Kinase Selectivity Analysis | 241 | ||
| 9.4 Safety Screening Strategies for Kinase Inhibitors | 243 | ||
| 9.5 In Situ Kinase Profiling | 247 | ||
| 9.6 Species Selection for In Vivo Safety Studies | 248 | ||
| 9.7 Summary and Future Outlook | 249 | ||
| References | 250 | ||
| Chapter 10 - Drugging the Kinome | 253 | ||
| 10.1 Introduction | 253 | ||
| 10.2 Factors that Will Allow Us to Find Useful Inhibitors for Each Kinase | 254 | ||
| 10.2.1 Motivation: Reasons that Direct Community Behavior Towards Complete Kinome Coverage | 254 | ||
| 10.2.1.1 Track Record of Success | 254 | ||
| 10.2.1.2 There Are Many Kinases Involved in Disease Biology for Which There is No Drug, and in Many Instances No Selective Tool | 254 | ||
| 10.2.1.3 Having Such a Tool Set Will Help Us Identify the Best Kinase Targets More Efficiently | 256 | ||
| 10.2.2 Opportunity: Contextual and Situational Factors that Position Us to Achieve Complete Kinome Coverage | 256 | ||
| 10.2.2.1 A Broad (and Growing) Knowledge Base Is in Place | 256 | ||
| 10.2.2.1.1\rKnowledge Base: Availability of Extensive Screening Data.Multiple groups have published the results of screening sets of compoun... | 257 | ||
| 10.2.2.1.2\rKnowledge Base: Kinase Crystal Structures.Currently, structural information is available in the Protein Data Bank (PDB)27 for ap... | 257 | ||
| 10.2.2.2 The Need for and Benefits of Collaboration in Science Are Being Increasingly Recognized | 259 | ||
| 10.2.3 Ability: Skills and Capabilities Requisite for Community to Attain Complete Kinome Coverage | 260 | ||
| 10.3 Approved Kinase Drugs | 261 | ||
| 10.4 Kinase Chemical Probes from the Chemical Probes Portal | 262 | ||
| 10.5 Kinases Covered by Narrow Spectrum Inhibitors (Not Necessarily Probe Quality) | 265 | ||
| 10.6 Uncovered Kinases (No Narrow Spectrum Inhibitor Identified) | 267 | ||
| 10.7 Next Step Challenge: Kinome Wide Cellular Screening | 271 | ||
| 10.8 Summary and Future Prospects | 273 | ||
| References | 274 | ||
| Chapter 11 - The Importance of Kinase Mutations in Cancer Drug Discovery | 281 | ||
| 11.1 Background | 281 | ||
| 11.2 Kinases as Drug Targets in Cancer | 282 | ||
| 11.2.1 Activating or Driver Mutations | 282 | ||
| 11.2.2 Kinase Fusions | 283 | ||
| 11.2.3 Upstream Pathway Activation | 283 | ||
| 11.2.4 Protein Overexpression or Gene Amplification | 284 | ||
| 11.2.5 Resistance Mutations | 284 | ||
| 11.3 Examples of Targeting Kinase Mutations in Drug Discovery | 284 | ||
| 11.3.1 Bcr–Abl | 285 | ||
| 11.3.2 EGFR | 290 | ||
| 11.3.3 ALK and ROS1 | 295 | ||
| 11.3.4 bRAF | 298 | ||
| 11.3.5 cKIT, PDGFα and FLT3 | 299 | ||
| 11.3.6 TRK | 302 | ||
| 11.3.7 RET | 303 | ||
| 11.4 Conclusions | 305 | ||
| References | 305 | ||
| Chapter 12 - Kinase Inhibition for Immuno-oncology | 313 | ||
| 12.1 Introduction | 313 | ||
| 12.2 Tyrosine Kinases | 314 | ||
| 12.2.1 CSF-1R (FMS) | 314 | ||
| 12.2.2 RON | 318 | ||
| 12.2.3 TAM Receptors | 320 | ||
| 12.2.4 FAK (PTK2) | 324 | ||
| 12.2.5 TIE2 | 326 | ||
| 12.2.6 BRAF/MEK | 327 | ||
| 12.3 Serine/Threonine Kinases | 328 | ||
| 12.3.1 TGF-βRI/ALK5 | 328 | ||
| 12.3.2 CDK4/6 | 331 | ||
| 12.3.3 GSK3 | 332 | ||
| 12.4 Phosphatidylinositol Kinases | 332 | ||
| 12.4.1 PI3K-delta | 333 | ||
| 12.4.2 PI3K-gamma | 338 | ||
| 12.4.3 PI3K-beta | 340 | ||
| 12.5 Conclusions | 343 | ||
| References | 344 | ||
| Chapter 13 - A Structural Perspective of the Pseudokinome: Defining the Targetable Space | 359 | ||
| 13.1 Background: the Discovery of Non-catalytic Functions Within the Kinome | 359 | ||
| 13.2 Pseudokinomes and Disease | 360 | ||
| 13.3 Analysis of the Kinase/Pseudokinase Core Architecture | 362 | ||
| 13.3.1 The Kinase Fold | 362 | ||
| 13.3.2 The Pseudokinase Fold | 363 | ||
| 13.3.2.1 Pseudokinases with a Degraded Nucleotide Binding Site | 364 | ||
| 13.3.2.2. Pseudokinases with Intact Nucleotide Binding Sites | 367 | ||
| 13.4 Regulatory Mechanisms Employed by Pseudokinases | 367 | ||
| 13.4.1 Pseudokinases that Interact with Known Kinase Partners | 367 | ||
| 13.4.2 Pseudokinases that Interact with Non-kinase Partners | 370 | ||
| 13.5 Current Initiatives to Target Pseudokinases | 372 | ||
| 13.6 Conclusions | 375 | ||
| Acknowledgements | 375 | ||
| References | 376 | ||
| Chapter 14 - The Future of Kinase Therapeutics | 381 | ||
| 14.1 Introduction | 381 | ||
| 14.2 Kinase Activators as a Therapeutic Modality | 382 | ||
| 14.3 Induced Protein Degradation | 388 | ||
| 14.4 Emerging Opportunities to Design More Effective Therapies for Cancer | 393 | ||
| References | 398 | ||
| Subject Index | 406 |