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. KRASAnalyzes medicinal chemistry case histories for seminal contributions to the KRAS fieldProvides an overview of in vitro and in vivo methods for drugging KRAS INDICE: 1. Introduction to KRAS Biology 2. Historical context and background to RAS drug discovery: the first 25 years of RAS targeting focused on FTase inhibitors 3. KRAS in vitro assays - biochem, biophysics and cell based 4. KRAS in vivo models and pharmacology 5. RAS Structural Biology: The Journey from Structures to Therapeutic Advances Section 1: First generation KRAS G12C OFF inhibitors 6. ARS-1620 SAR journey 7. Sotorasib/AMG510 SAR journey 8. Adagrasib/MRTX849 SAR journey 9. Novartis SAR journey - JDQ 443 10. Jacobio SAR Journey - JAB-21822 11. KRAS degraders Section 2: Second generation G12C inhibitors and new modalities 12. KRAS ON inhibitors using Tri-complex inhibitors - RMC-4998/6291 story Section 3: Beyond KRAS G12C 13. Pan-KRAS inhibitors 14. RAS-multi - RMC-7977 story 15. G12S/R stories 16. G12D stories 17. MRTX1133 (small molecule) 18. RMC-9945 (G12D covalent inhibitor) 19. KRAS combinations (preclinical and clinical) 20. The immune-oncology potential of KRAS inhibitors 21. KRAS Competitive Intelligence/G12C, G12D, pan/multi-RAS Chapter 22. Conclusions and future of RAS Drug Discovery 23. LUMAKRAS® (sotorasib): SAR Journey & Path to the Clinic
- ISBN: 978-0-443-21861-3
- Editorial: Elsevier
- Encuadernacion: Rústica
- Páginas: 562
- Fecha Publicación: 01/11/2024
- Nº Volúmenes: 1
- Idioma: Inglés