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.
Table of Contents
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
Authors
Adrian Gill SVP Discovery Chemistry, Revolution Medicines Inc., USA. Adrian has over 25 years of drug discovery and development experience in senior roles across a diverse range of disease areas in both large pharma and biotech environments and been heavily involved in the identification of multiple clinical candidates across a variety of disease areas. He is a co-inventor of RMC-4630, Revolution Medicines first development candidate selectively targeting SHP2 and RMC-5552, a bi-steric inhibitor which selectively targets mTORC1. Adrian has been instrumental in the design and development of four more recent RAS(ON) development candidates from the Revolution Medicines tri-complex inhibitor platform and is also a co-inventor of RMC-6236 (RAS MULTI inhibitor), RMC-6291(KRASG12C inhibitor), RMC-8839 (KRASG13C inhibitor) and RMC-9805(KRASG12D inhibitor).Adrian has authored over 25 publications in peer-reviewed journals, is a named inventor on over 45 issued and pending small molecule patent applications and has given multiple invited presentations at national and international conferences. Adrian received his Ph.D. in organic chemistry from the University of Sussex, U.K. and has a bachelor's degree in applied chemistry from the University of Salford, U.K. Adrian is a member of the Royal Society of Chemistry, the SCI, the American Chemical Society and an invited member of the AACR Chemistry in Cancer Research (CICR) Steering Committee. Adrian is also a member of XPose Therapeutics and Curve Therapeutics scientific advisory boards and an honorary Prof. of Drug Discovery at the Sussex University Drug Discovery Center, UK. Kevan M Shokat Department of Cellular and Molecular Pharmacology at UCSF; Professor of Chemistry at UC Berkeley; Howard Hughes Medical Institute investigator, USA. Professor Kevan is currently an Investigator of the Howard Hughes Medical Institute, Chair of the Department of Cellular and Molecular Pharmacology at UCSF and a Professor of Chemistry at UC Berkeley. He was inducted into the National Academy of Sciences (2010), the Institute of Medicine (2011), and the American Academy of Arts and Sciences (2011). His lab is most well-known for drugging the "undruggable" oncogene K-Ras (G12C) in 2013. In May of 2021 the drug sotorasib which binds to the same pocket on K-Ras (G12C) was approved for the treatment of lung cancer patients with this mutation. The field of K-Ras drug discovery is expanding quickly to hunt for drugs to target the other K-Ras mutants such as those which drive colon and pancreatic cancers which collectively represent almost 20% of all cancer patients world-wide. Kevan has been a co-founder of a number companies from their inception to public offering or acquisition and he is a co-founder of several currently private companies.
