Discovery and In Vitro Characterization of Macrocyclic 2-(Heteroaryl)Pyrimidine Inhibitors Targeting Wild-Type KRAS and G12D/G12V Mutants

KRAS mutations are key drivers of oncogenesis in numerous cancer types, with KRASG12V, KRASG12D, and KRASG12C alterations being the most prevalent. While inhibitors targeting KRASG12C have shown clinical success, challenges remain in addressing the broader spectrum of KRAS mutations. Our initial effort to discover a broad-based KRAS therapeutic was guided by a scaffold-hopping campaign inspired by compounds with demonstrated switch-II pocket engagement. While macrocyclization of a 2-(1-pyrazolyl)pyrimidine core prototype did not yield suitable in vitro activity at the outset, it provided valuable insights into subsequent efforts. Refinement of our approach led to compound 1, which demonstrated high KRASG12V binding affinity and concomitant biochemical potency in KRASG12V/G12D mutants. Further physicochemical improvements led to the design of 2-(3-isoxazolyl)pyrimidine macrocycles with improved permeability and in vitro mutant KRAS cellular activity.