Mu
Table of Contents
Preface vii
Chapter 1. Introduction 1
1.1 Types of Protein Kinases 1
1.2 Protein Kinase Domains 1
1.3 ATP-Binding Site 2
1.4 Types of Kinase Inhibitors 3
1.5 Brief History of Smallmolecule Kinase Inhibitors 5
1.6 Peak 12-Month Sales for Leading Kinase Inhibitors 7
1.7 Approved Kinase Inhibitors 7
Chapter 2. BCR-ABL Inhibitors 18
2.1 Imatinib* (1) 19
2.2 Nilotinib* (2) 24
2.3 Dasatinib* (3) 27
2.4 Bosutinib* (4) 30
2.5 Ponatinib* (5) 33
2.6 Olvermbatinib** (6) 37
2.7 Asciminib* (7) 38
Chapter 3. BTK Inhibitors 43
3.1 Ibrutinib* (8) 45
3.2 Acalabrutinib* (9) 51
3.3 Zanubrutinib* (10) 54
3.4 Tirabrutinib** (11) 57
3.5 Orelabrutinib** (12) 58
Chapter 4. EGFR/HER Family Inhibitors 59
4.1 Gefitinib* (13) 61
4.2 Erlotinib * (14) 67
4.3 Icotinib** (15) 72
4.4 Afatinib* (16) 74
4.5 Dacomitinib* (17) 77
4.6 Osimertinib* (18) 80
4.7 Mobocertinib* (19) 86
4.8 Lapatinib* (20) 90
4.9 Tucatinib* (21) 93
4.10 Neratinib* (22) 95
Chapter 5. VEGFR/Multikinase Inhibitors 97
5.1 Sorafenib* (23) 99
5.2 Regorafenib* (24) 104
5.3 Sunitinib* (25) 106
5.4 Pazopanib* (26) 112
5.5 Axitinib* (27) 114
5.6 Nintedanib* (28) 117
5.7 Apatinib** (29) 121
5.8 Lenvatinib* (30) 122
5.9 Tovozanib* (31) 125
Chapter 6. CDK4/6 Inhibitors 127
6.1 Palbociclib* (32) 129
6.2 Ribociclib*(33) 136
6.3 Abemaciclib* (34) 139
6.4 Trilaciclib* (35) 142
Chapter 7. JAK Inhibitors 144
7.1 Tofacitinib* (36) 147
7.2 Baricitinib* (37) 151
7.3 Peficitinib** (38) 153
7.4 Upadacitinib* (39) 158
7.5 Delgocitinib** (40) 161
7.6 Filgotinib** (41) 163
7.7 Abrocitinib* (42) 166
7.8 Ruxolitinib* (43) 170
7.9 Fedratinib* (44) 173
7.10 Pacritinib* (45) 175
7.11 Ritlecitinib # (46) 177
7.12 Brepocitinib # (47) 181
7.13 Ropsacitinib # (48) 184
Chapter 8. Allosteric TYK2 Inhibitors 187
8.1 Deucravacitinib* (49) 189
Chapter 9. ALK/multikinase Inhibitors 195
9.1 Crizotinib* (50) 197
9.2 Ceritinib* (51) 202
9.3 Alectinib* (52) 205
9.4 Brigatinib* (53) 207
9.5 Lorlatinib* (54) 210
Chapter 10. BRAF/Multikinase Inhibitors 214
10.1 Vemurafenib* (55) 216
10.2 Dabrafenib* (56) 222
10.3 Encorafenib* (57) 225
Chapter 11. MEK Inhibitors 227
11.1 Trametinib* (58) 228
11.2 Cobimetinib* (59) 232
11.3 Binimetinib* (60) 235
11.4 Selumetinib* (61) 237
Chapter 12. RET/Multikinase Inhibitors 240
12.1 Vandetanib* (62) 242
12.2 Cabozantinib* (63) 245
12.3 Selpercatinib* (64) 247
12.4 Pralsetinib* (65) 251
Chapter 13. FGFR Inhibitors 253
13.1 Erdafitinib* (66) 255
13.2 Pemigatinib* (67) 260
13.3 Infigratinib* (68) 263
13.4 Futibatinib* (69) 265
Chapter 14. PI3K Inhibitors 267
14.1 Alpelisib* (70) 269
14.2 Idelalisib* (71) 273
14.3 Duvelisib* (72) 277
14.4 Umbralisib* (73) 279
14.5 Copanlisib* (74) 281
Chapter 15. TRK/Multikinase Inhibitors 284
15.1 Larotrectinib* (75) 285
15.2 Entrectinib* (76) 288
15.3 Repotrectinib # (77) 291
Chapter 16. MET Inhibitors 294
16.1 Capmatinib* (78) 295
16.2 Tepotinib* (79) 297
Chapter 17. KIT/PDGFR/Multkinase Inhibitors 299
17.1 Avapritinib* (80) 301
17.2 Ripretinib* (81) 304
Chapter 18. FLT3 Inhibitors 306
18.1 Midostaurin* (82) 308
18.2 Gilteritinib* (83) 313
Chapter 19. mTOR Inhibitors 315
19.1 Sirolimus* and Analogs (84) 317
Chapter 20. Other Kinase Inhibitors 322
20.1 Netarsudil* (85) 324
20.2 Belumosudil* (86) 326
20.3 Fostamatinib* (87) 328
20.4 Pexidartinib* (88) 331
Chapter 21. KRAS Inhibitors 335
21.1 Sotorasib* (89) 337
21.2 Adagrasib* (90) 346
21.3 Jdq443 # (91) 350
Chapter 22. An Overview of the Discovery Process for Medically Useful Inhibitors of Oncogenic Protein Kinases 353
22.1 High-quality Leads 353
22.2 Integrating Substructures from Different High Quality Leads or Established Inhibitors 355
22.3 Variation of Hinge-binding Nucleus 357
22.4 Macrocyclization 359
22.5 Fragment-based Approach 360
22.6 Covalent Inhibitors 361
22.7 Strategic Structural Modification of Prior Drugs 362
22.8 Exploiting a Specific Kinase Pocket to Optimize Selectivity 364
22.9 Solvent-exposed Appendages to Enhance Solubility and PK Properties 367
Chapter 23. Targeted Molecular Anticancer Therapies – Successes and Challenges 368
23.1 The Beginning 368
23.2 Further Developments 368
23.3 Biomarker-driven Drug Development 369
23.4 Mitigation of Drug Resistance 370
23.5 Miscellaneous Approaches 371
23.6 Discovery Chemistry 373
Appendix 1. First FDA Approvals by Year 374
Appendix 2. Kinase/KRAS Inhibitors in Development 375
Appendix 3. Visualization of Differentially Expressed Kinases in Cancer 378
Appendix 4. M & A Transactions Driven by Oncology-focused Kinase and KRAS Inhibitors 379
Appendix 5. Alphabetic List of Oncogenic Protein Inhibitors 380
