RAS Drug Discovery

Past, Present and Future

Adrian Gill, Kevan M Shokat, Kevan M. Shokat

• Publisher: Elsevier
• Year: 2024
• Topic: Physical Sciences
• eBook ISBN:
  9780443218620
• Subtopic: Chemistry
• Index: Chemistry

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

• Cover
• Front Matter
• Table of Contents
• Copyright
• Contributors
• Editor biographies
• RAS Hall of Fame
• Foreword
• Preface
• Personal acknowledgements
• Introduction
• List of Illustrations
• List of Tables
• 1 : Introduction to RAS biology
• 2 : Targeting RAS membrane association
• 3 : Advancing KRAS drug discovery: A deep dive into biochemical, biophysical, and cellular assays for the identification and optimization of KRAS inhibitors
• 4 : KRAS-driven cancer models for in vivo pharmacology and drug discovery
• 5 : The evolution of RAS structural biology: From structures to therapeutic advances
• 6 : Covalently targeting KRAS G12C: From inception to the first in vivo proof of concept with ARS-1620
• 7 : LUMAKRAS® (sotorasib): Novel strategies and clinical experience
• 8 : Discovery and development of Krazati (adagrasib/MRTX849), a potent, selective, orally bioavailable, covalent KRASG12C(OFF) inhibitor
• 9 : Discovery of JDQ443 (opnurasib): A structurally diverse KRASG12C inhibitor
• 10 : KRAS degraders
• 11 : Discovery of RMC-6291, a potent, orally bioavailable, covalent RAS(ON) G12C selective inhibitor
• 12 : The emergence of pan-KRAS drugs
• 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
• 14 : LUNA18, a macrocyclic orally bioavailable peptide pan-RAS inhibitor, discovered from a beyond rule of 5 drug discovery platform
• 15 : Covalent inhibitors of K-Ras G12S, G12R, and G12D
• 16 : Discovery and development of MRTX1133, a potent, selective, noncovalent inhibitor of KRASG12D
• 17 : KRAS combination strategies: How well aligned is clinical and preclinical research?
• 18 : Immune-oncology potential of KRAS inhibitors
• 19 : The RAS competitive landscape
• 20 : Conclusions: the future of RAS drug discovery
• Index
• A