A comprehensive review of the latest molecular advances in cancer treatment
Featuring 91 total small molecule kinase/KRAS inhibitors, 80 of which are FDA-approved, Molecules Engineered Against Oncogenic Proteins and Cancer documents the recent scientific advances that have transformed one of medicine’s most challenging areas - cancer treatment. Most of these inhibitors specifically block oncogene-induced carcinogenic proteins with results that have dramatically advanced the treatment of cancer. In addition, the structural formulas of more than 100 kinase/KRAS inhibitors in clinical trials are presented.
With a very well-known chemist as an author, Molecules Engineered Against Oncogenic Proteins and Cancer includes information on: - Each molecule’s structure, function of the kinase target and relevance to cancer, the drug discovery process, and molecular details of drug action - Mutated protein kinases as oncoproteins and targets for inhibition, along with the details of discovery for each antitumor antikinase agent - History of oncoprotein inhibitors and their role in advancing the treatment and understanding of cancer - The discovery process as a whole, effective strategies for innovation, ongoing challenges, and a glimpse of the future of the field
Combining the most significant recent discoveries in a unique and useful way, Molecules Engineered Against Oncogenic Proteins and Cancer is an essential resource for researchers and students in bioscience, medicine, chemistry, and oncology as well as for those at industrial companies involved in therapeutic discovery.
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
