Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRASG12D Mutation.

Effective oral therapies are urgently required to treat KRASG12D mutant cancers. Therefore, synthesis and screening were performed for 38 prodrugs of MRTX1133 to identify an oral prodrug of MRTX1133, a KRASG12D mutant protein-specific inhibitor. In vitro and in vivo evaluations revealed prodrug 9 as the first orally available KRASG12D inhibitor. Prodrug 9 exhibited improved pharmacokinetic properties for the parent compound in mice and was efficacious in a KRASG12D mutant xenograft mouse tumor model after oral administration.