3:00 PM: "Design and Synthesis of the Macrocyclic pan-KRAS Inhibitor AMG 410" (Ryan Wurz)

KRAS is the most frequently mutated oncogene, with mutations found in over 20% of human cancers, including pancreatic, colorectal, and lung, endometrial, and gastric tumors. Building on key insights from the development of sotorasib, a covalent KRAS G12C inhibitor, we applied structure- and property-based design strategies to identify a new class of reversible, macrocyclic pan-KRAS inhibitors. This presentation describes the design rationale and synthetic approaches used to access these potent inhibitors and examines the structure-activity relationships that guided program evolution. These efforts culminated in the discovery of AMG 410, which is currently under clinical evaluation in patients harboring KRAS missense mutations or genetic amplifications who have progressed on standard-of-care therapies.

4:00 PM: "Fluorination under Hydrogen Bonding Phase-transfer Catalysis" (Veronique Gouverneur)

The economic impact of catalysis is significant contributing 30–40% of global GDP. In this context, phase-transfer catalysis is a powerful manifold for asymmetric synthesis. Chiral cationic or anionic PTC strategies have enabled a variety of transformations, yet studies on the use of insoluble inorganic salts as nucleophiles for the synthesis of enantioenriched molecules have remained elusive. A long-standing challenge is the development of methods for asymmetric carbon–fluorine bond formation from cost-effective alkali metal fluorides. In this lecture, we will describe how hydrogen-bond donor catalysts can provide a solution to enantioselective nucleophilic fluorination through controlled fluoride binding.