KRAS Drug Discovery: Past, Present and Future is a comprehensive overview of the state-of-the-art medicinal chemistry approaches towards targeting the formerly undruggable oncogene, KRAS. It includes Seminal medicinal chemistry case histories of KRASG12C inhibitors such as Sotorosib, the first approved KRASG12C inhibitor for NSCLC, alongside the latest advances towards identification of in vivo tools and development candidates targeting KRAS G12D, KRAS G13C and other mutations. The book also provides the reader with a comprehensive overview of the in vitro assay systems, in vivo pharmacology xenograft models and chemical biology tools available to characterize small molecule inhibitors of KRAS.
1. Introduction - p. Page xix 2. List of Illustrations - p. Page xxiii 3. List of Tables - p. Page xxiv 4. 1 : Introduction to RAS biology - p. Page xxiv 5. 2 : Targeting RAS membrane association - p. Page 26 6. 3 : Advancing KRAS drug discovery: A deep dive into biochemical, biophysical, and cellular assays for the identification and optimization of KRAS inhibitors - p. Page 52 7. 4 : KRAS-driven cancer models for in vivo pharmacology and drug discovery - p. Page 86 8. 5 : The evolution of RAS structural biology: From structures to therapeutic advances - p. Page 112 9. 6 : Covalently targeting KRAS G12C: From inception to the first in vivo proof of concept with ARS-1620 - p. Page 139 10. 7 : LUMAKRAS® (sotorasib): Novel strategies and clinical experience - p. Page 170 11. 8 : Discovery and development of Krazati (adagrasib/MRTX849), a potent, selective, orally bioavailable, covalent KRASG12C(OFF) inhibitor - p. Page 200 12. 9 : Discovery of JDQ443 (opnurasib): A structurally diverse KRASG12C inhibitor - p. Page 224 13. 10 : KRAS degraders - p. Page 245 14. 11 : Discovery of RMC-6291, a potent, orally bioavailable, covalent RAS(ON) G12C selective inhibitor - p. Page 268 15. 12 : The emergence of pan-KRAS drugs - p. Page 302 16. 13 : Development of RMC-6236, a potent and orally bioavailable RAS(ON) multi-selective tri-complex inhibitor for the treatment of RAS-addicted cancers by targeting multiple RAS variants - p. Page 336 17. 14 : LUNA18, a macrocyclic orally bioavailable peptide pan-RAS inhibitor, discovered from a beyond rule of 5 drug discovery platform - p. Page 356 18. 15 : Covalent inhibitors of K-Ras G12S, G12R, and G12D - p. Page 375 19. 16 : Discovery and development of MRTX1133, a potent, selective, noncovalent inhibitor of KRASG12D - p. Page 399 20. 17 : KRAS combination strategies: How well aligned is clinical and preclinical research? - p. Page 415 21. 18 : Immune-oncology potential of KRAS inhibitors - p. Page 436 22. 19 : The RAS competitive landscape - p. Page 457 23. 20 : Conclusions: the future of RAS drug discovery - p. Page 490 24. Index - p. Page 502
KRAS Drug Discovery: Past, Present and Future is a comprehensive overview of the state-of-the-art medicinal chemistry approaches towards targeting the formerly undruggable oncogene, KRAS. It includes Seminal medicinal chemistry case histories of KRASG12C inhibitors such as Sotorosib, the first approved KRASG12C inhibitor for NSCLC, alongside the latest advances towards identification of in vivo tools and development candidates targeting KRAS G12D, KRAS G13C and other mutations. The book also provides the reader with a comprehensive overview of the in vitro assay systems, in vivo pharmacology xenograft models and chemical biology tools available to characterize small molecule inhibitors of KRAS.
1. Introduction - p. Page xix 2. List of Illustrations - p. Page xxiii 3. List of Tables - p. Page xxiv 4. 1 : Introduction to RAS biology - p. Page xxiv 5. 2 : Targeting RAS membrane association - p. Page 26 6. 3 : Advancing KRAS drug discovery: A deep dive into biochemical, biophysical, and cellular assays for the identification and optimization of KRAS inhibitors - p. Page 52 7. 4 : KRAS-driven cancer models for in vivo pharmacology and drug discovery - p. Page 86 8. 5 : The evolution of RAS structural biology: From structures to therapeutic advances - p. Page 112 9. 6 : Covalently targeting KRAS G12C: From inception to the first in vivo proof of concept with ARS-1620 - p. Page 139 10. 7 : LUMAKRAS® (sotorasib): Novel strategies and clinical experience - p. Page 170 11. 8 : Discovery and development of Krazati (adagrasib/MRTX849), a potent, selective, orally bioavailable, covalent KRASG12C(OFF) inhibitor - p. Page 200 12. 9 : Discovery of JDQ443 (opnurasib): A structurally diverse KRASG12C inhibitor - p. Page 224 13. 10 : KRAS degraders - p. Page 245 14. 11 : Discovery of RMC-6291, a potent, orally bioavailable, covalent RAS(ON) G12C selective inhibitor - p. Page 268 15. 12 : The emergence of pan-KRAS drugs - p. Page 302 16. 13 : Development of RMC-6236, a potent and orally bioavailable RAS(ON) multi-selective tri-complex inhibitor for the treatment of RAS-addicted cancers by targeting multiple RAS variants - p. Page 336 17. 14 : LUNA18, a macrocyclic orally bioavailable peptide pan-RAS inhibitor, discovered from a beyond rule of 5 drug discovery platform - p. Page 356 18. 15 : Covalent inhibitors of K-Ras G12S, G12R, and G12D - p. Page 375 19. 16 : Discovery and development of MRTX1133, a potent, selective, noncovalent inhibitor of KRASG12D - p. Page 399 20. 17 : KRAS combination strategies: How well aligned is clinical and preclinical research? - p. Page 415 21. 18 : Immune-oncology potential of KRAS inhibitors - p. Page 436 22. 19 : The RAS competitive landscape - p. Page 457 23. 20 : Conclusions: the future of RAS drug discovery - p. Page 490 24. Index - p. Page 502
