Kinase drug discovery remains an area of significant interest across academia and in the pharmaceutical industry. There are now around 13 FDA approved small molecule drugs which target kinases and many more compounds in various stages of clinical development. Although there have been a number of reviews/publications on kinase research, this book fills a gap in the literature by considering the current and future opportunities and challenges in targeting this important family of enzymes. The book is forward-looking and identifies a number of hot topics and key areas for kinase drug discovery over the coming years. It includes contributions from highly respected authors with a combined experience in the industry of well over 200 years, which has resulted in a book of great interest to the kinase field and across drug discovery more generally. Readers will gain a real insight into the huge challenges and opportunities which this target class has presented drug discovery scientists. The many chapters cover a wide breadth of topics, are well written and include high quality colour and black and white images. Topics covered include an outline of how medicinal chemistry has been able to specifically exploit this unique target class, along with reflections on the mechanisms of kinases inhibitors. Also covered is resistance to kinase inhibitors caused by amino acid mutations, case studies of kinase programs and reviews areas beyond protein kinases and beyond the human kinome. Also described are modern approaches to finding kinase leads and the book finishes with a reflection of how kinase drug discovery may progress over the coming years.
Author(s): Richard A. Ward, Frederick W. Goldberg
Series: RSC Drug Discovery 19
Publisher: Royal Society of Chemistry
Year: 2012
Language: English
Pages: xiv+318
Kinase Drug Discovery......Page 4
Preface......Page 6
Contents......Page 10
1.1 Introduction......Page 16
1.2 Kinome Scale Assays......Page 23
1.3 Starting Points for Kinase Probe Discovery: The benefits of chemical connectivity......Page 31
1.4 Measures of Selectivity......Page 36
1.5 Examples of Selectivity Improvement......Page 38
References......Page 41
Appendix 1.1: Selection of suppliers of commercially available kinase assay for compound screening......Page 45
2.1 Introduction......Page 69
2.2 Isoform Selective, PH Domain Dependent Akt Inhibitors......Page 70
2.3 Exploitation of Inactive Kinase Conformations......Page 72
2.3.1 Switch Pocket Inhibitors......Page 73
2.3.2 Hydrophobic Motifs......Page 76
2.4 Targeted Kinase Libraries......Page 80
2.5.1 Scaffold-Hopping and Hybridisation......Page 81
2.5.2 Fragment-Based Lead Generation......Page 85
2.5.3 Virtual Screening......Page 88
References......Page 90
3.1 Introduction......Page 94
3.2 Structural Basis of Kinase Inhibition and its Effects on Selectivity......Page 95
3.3 Translating Isolated Enzyme Inhibition to Efficacy Against the Native Kinase......Page 103
3.4 Solubility as a Key Developability Property......Page 105
3.5 Intellectual Property Considerations......Page 106
References......Page 108
4.1 Introduction......Page 111
4.2.2 Binding Modes for Early Kinase Inhibitors......Page 112
4.2.3 Diverse Binding Modes for Recent Kinase Inhibitors......Page 116
4.3 Kinetics of Inhibition......Page 118
4.3.1 ATP-Dependence......Page 119
4.3.2 Rates for Onset and Reversal of Inhibition......Page 120
4.3.3 Tight Binding Inhibition......Page 121
4.3.4 Binding Assays......Page 122
4.3.5 Relationships Between IC50, Ki and Kd......Page 124
4.4.1.1 Design of Hit Identification Assays......Page 125
4.4.1.2 Evaluation of Inhibitors......Page 126
4.4.1.3 Mechanisms and SAR......Page 127
4.4.1.4 Structure-Based Design......Page 128
4.4.2.1 Efficacy for Rapidly Reversible Inhibitors......Page 129
4.4.2.2 Inhibitor Selectivity......Page 131
4.4.2.4 Slowly Reversible and Irreversible Inhibitors......Page 132
4.4.2.6 Covalent Inhibitors......Page 133
4.4.2.8 Patient Selection in Cancer Therapy......Page 134
4.5 Conclusions......Page 135
References......Page 136
5.1 Introduction......Page 141
5.1.1 Kinase activation......Page 144
5.1.2 Type I, Type II and Type III inhibitors......Page 146
5.2 Kinases inhibited by imatinib......Page 147
5.2.1 Resistance mutations to imatinib and successor compounds (BCR-Abl)......Page 148
5.2.2 Resistance mutations to imatinib and successor compounds (KIT kinase)......Page 150
5.2.3 Design strategies to overcome resistance mutations......Page 151
5.3.1 Activating mutations leading to drug susceptibility......Page 154
5.3.3 Inhibitors and design strategies......Page 156
5.4 Preclinical prediction of kinase resistance mutations......Page 159
5.5 Resistance mechanisms not involving kinase domain mutations......Page 162
5.6 Outlook......Page 166
References......Page 168
6.1 Introduction......Page 176
6.2.1 Hexokinases (HK)......Page 177
6.2.3 6-Phosphofructo-2-kinase–Fructose-2,6-bisphosphatase (PFK2–FBPase2)......Page 178
6.3.1 Uridine-cytidine Kinase......Page 179
6.3.2 Thymidine Kinase......Page 180
6.3.3 Deoxycytidine Kinase......Page 181
6.3.4 Adenosine Kinase......Page 182
6.3.4.1 Abbott Inhibitors......Page 183
6.3.4.2 Gensia Sicor – Metabasis Inhibitors......Page 184
6.3.4.3 Other Inhibitors......Page 185
6.3.5 Conclusion......Page 187
6.4.1.1 PI3K-α Inhibitors, pan-PI3K Inhibitors and Dual mTOR–PI3K-α Inhibitors......Page 188
6.4.1.2 Inhibitors of Other PI3K Isoforms......Page 197
6.4.1.3 mTOR Inhibitors......Page 200
6.4.1.4 Other PIKKs......Page 204
6.4.2.1 Inositol 1,4,5-trisphosphate 3-kinase (Itpk)......Page 208
6.4.2.3 Phosphatidylinositol 4-phosphate 5-kinase (PIP5K)......Page 209
6.4.3.2 Choline Kinase (CHK)......Page 210
6.4.3.3 Ceramide Kinase (CERK)......Page 211
6.4.3.4 Sphingosine Kinase Inhibitors......Page 212
6.5.1 Mevalonate Kinase......Page 215
6.5.2 Pyruvate Kinase (PK)......Page 216
6.6 Conclusion......Page 217
References......Page 218
7.1 Introduction......Page 233
7.2 Inhibitors of Rho Kinase – fasudil......Page 236
7.3 Inhibitors of p38α......Page 237
7.4 Inhibitors of SYK......Page 242
7.5 Inhibitors of PKC......Page 244
7.6 Inhibitors of JAK......Page 245
7.8 Multikinase Inhibitors......Page 251
7.9 Inhibitors of Bcr-Abl, c-Kit and PDGFR – Imatinib (Gleevec®) and Nilotinib (Tasigna)......Page 252
References......Page 254
8.1 Introduction......Page 259
8.2 Glucokinase Structure and Function......Page 260
8.3 The Initial Discovery of Small Molecule GK Activators......Page 262
8.4 Recent Advancements in the Identification of Small Molecule GK Activators......Page 265
8.5 Selected Novel Glucokinase Activator Structures from Recent Patent Literature......Page 269
References......Page 274
9.1 The Burden of Human Parasitic Diseases......Page 277
9.2 Non-Human Kinomes......Page 278
9.3 Kinetoplastids......Page 279
9.4.1 Malaria......Page 280
9.4.2.1 The AGC Group......Page 282
9.4.2.5 The NIMA Group......Page 284
9.4.2.7 Other–Orphan......Page 285
9.5.1 Will P. falciparum Kinase Inhibitors Work as Anti-Malarial Drugs?......Page 286
9.5.3.1 Current Best Practice and the Eradication Agenda......Page 287
9.5.3.2 Functional Genomics......Page 288
9.5.3.3 Host Kinases......Page 289
9.6.1 Structural Biology......Page 290
9.7 Chemical Biology and Drug Discovery Programmes......Page 292
9.7.1 In Vitro Screening of Validated Plasmodium Kinases......Page 293
9.7.2 ‘‘Malaria Boxes’’......Page 295
References......Page 296
10.2 Overcoming resistance......Page 301
10.2.1 Irreversible kinase inhibitors......Page 302
10.2.2 Optimizing target modulation and pharmacological properties......Page 305
10.2.3 Polypharmacological inhibitors and combinations thereof......Page 307
10.3 Magic bullets and new chemical space......Page 310
10.4.1 Kinase activation—a new paradigm in drug discovery......Page 311
10.4.2 Pseudokinases—new kids on the block......Page 312
10.5 Outlook......Page 313
References......Page 314
Subject Index......Page 318
