Macrocyclic heteroaryl-pyrimidines target wild-type KRAS and G12D/G12V mutants
- A scaffold-hopping effort, inspired by known switch-II pocket binders, aimed to build inhibitors covering KRAS variants beyond G12C.
- Macrocyclizing a pyrazolyl-pyrimidine prototype initially gave poor in vitro activity, but the findings informed a refined design.
- The resulting lead bound KRAS G12V tightly and showed matching biochemical potency against G12V and G12D.
- Switching to isoxazolyl-pyrimidine macrocycles improved permeability and cellular activity in mutant KRAS cells.
💡 Points
Equal biochemical potency on G12V and G12D suggests the macrocycle grips something shared rather than mutant-specific residues, which is the intriguing part. Before I would call this a usable pan-KRAS series, though, I need wild-type data, since selectivity and on-target tolerability remain open. The isoxazole swap that rescued permeability is a practical fix, but the starting scaffold looks crowded.