Description
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.- Highlights key structure-based drug design (SBDD) innovations to generate potency and selectivity vs. KRAS- Analyzes medicinal chemistry case histories for seminal contributions to the KRAS field- Provides an overview of in vitro and in vivo methods for drugging KRAS
Table of Contents
1. Introduction to KRAS Biology2. Historical context and background to RAS drug discovery: the first 25 years of RAS targeting focused on FTase inhibitors3. KRAS in vitro assays – biochem, biophysics and cell based4. KRAS in vivo models and pharmacology5. RAS Structural Biology: The Journey from Structures to Therapeutic AdvancesSection 1: First generation KRAS G12C OFF inhibitors6. ARS-1620 SAR journey7. Sotorasib/AMG510 SAR journey8. Adagrasib/MRTX849 SAR journey9. Novartis SAR journey - JDQ 44310. Jacobio SAR Journey – JAB-2182211. KRAS degradersSection 2: Second generation G12C inhibitors and new modalities12. KRAS ON inhibitors using Tri-complex inhibitors – RMC-4998/6291 storySection 3: Beyond KRAS G12C13. Pan-KRAS inhibitors14. RAS-multi – RMC-7977 story15. G12S/R stories16. G12D stories17. MRTX1133 (small molecule)18. RMC-9945 (G12D covalent inhibitor)19. KRAS combinations (preclinical and clinical)20. The immune-oncology potential of KRAS inhibitors21. KRAS Competitive Intelligence/G12C, G12D, pan/multi-RAS Chapter22. Conclusions and future of RAS Drug Discovery23. LUMAKRAS® (sotorasib): SAR Journey & Path to the Clinic
