Details

Molecules Engineered Against Oncogenic Proteins and Cancer

Discovery, Design, and Development
1. Aufl.

von: E. J. Corey, Yong-Jin Wu
189,99 €
Verlag:	Wiley
Format:	PDF
Veröffentl.:	09.08.2023
ISBN/EAN:	9781394207091
Sprache:	englisch
Anzahl Seiten:	400

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Beschreibungen

Titelbeschreibung

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: <ul><li>Each molecule’s structure, function of the kinase target and relevance to cancer, the drug discovery process, and molecular details of drug action</li> <li>Mutated protein kinases as oncoproteins and targets for inhibition, along with the details of discovery for each antitumor antikinase agent</li> <li>History of oncoprotein inhibitors and their role in advancing the treatment and understanding of cancer</li> <li>The discovery process as a whole, effective strategies for innovation, ongoing challenges, and a glimpse of the future of the field</li></ul> 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.

Inhaltsverzeichnis

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

Autorenportrait

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.

Back cover copy

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: <ul><li>Each molecule’s structure, function of the kinase target and relevance to cancer, the drug discovery process, and molecular details of drug action</li> <li>Mutated protein kinases as oncoproteins and targets for inhibition, along with the details of discovery for each antitumor antikinase agent</li> <li>History of oncoprotein inhibitors and their role in advancing the treatment and understanding of cancer</li> <li>The discovery process as a whole, effective strategies for innovation, ongoing challenges, and a glimpse of the future of the field</li></ul> 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.