RAS Drug Discovery

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. 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.

• 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