Abstract
Effective oral therapies are urgently required to treat KRAS(G12D) mutant cancers. Therefore, synthesis and screening were performed for 38 prodrugs of MRTX1133 to identify an oral prodrug of MRTX1133, a KRAS(G12D) mutant protein-specific inhibitor. In vitro and in vivo evaluations revealed prodrug 9 as the first orally available KRAS(G12D) inhibitor. Prodrug 9 exhibited improved pharmacokinetic properties for the parent compound in mice and was efficacious in a KRAS(G12D) mutant xenograft mouse tumor model after oral administration.