Molecules Engineered Against Oncogenic Proteins and Cancer Discovery, Design, and Development

by Corey, E. J.; Wu, Yong-Jin

• ISBN13: 9781394207084
• ISBN10: 1394207085
• Edition: 1st
• Format: Hardcover
• Copyright: 2023-09-26
• Publisher: Wiley

Summary

Molecules Engineered Against Oncogenic Proteins and Cancer

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.

Author Biography

E. J. Corey has been a Professor at Harvard University since 1959. He was educated at The Massachusetts Institute of Technology (1945-1950) and served as a faculty member at the University of Illinois from 1951 to 1959. He is the 1990 Nobel Laureate in Chemistry. He has received many international awards including the U.S. National Medal of Science, the Japan Prize, the Wolf Prize and the Priestley Medal of the American Chemical Society, and many honorary degrees including DSc degrees from Oxford and Cambridge. He is a member of the U.S. National Academy of Sciences and the U.S. National Academy of Medicine. Professor Corey is the author of more than 1,000 publications and is one of the most cited authors in science. Among his previous books are The Logic of Chemical Synthesis (1989), Molecules and Medicine (2007) and Enantioselective Chemical Synthesis (2010).

Yong-Jin Wu is a medicinal chemist in the pharmaceutical industry with over 25 years of industry experience. He received his B.Sc. in chemistry from Hunan Normal University (Changsha, China) in 1983 and his Ph.D. in organic chemistry from Memorial University of Newfoundland in 1991 under Professor Jean Burnell. Subsequently, he undertook postdoctoral training in natural product synthesis with Professor Derrick Clive at the University of Alberta (1991-1992) and Professor E. J. Corey at Harvard University (1992-1995). He started his career as a medicinal chemist at Pfizer Central Research in Groton, CT in 1995 and joined Bristol Myers Squibb (BMS) in Wallingford, CT in 1999. He has been working at BMS ever since and currently is at the Cambridge, MA facility where his investigations focus on the discovery of novel kinase inhibitors for immunology, rheumatology and oncology indications.

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