Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS<sup>G12D</sup> Mutation
Xiang Ji, Yan Li, Xianqi Kong, Dawei Chen, Jiasheng Lu
Abstract
High Resolution Image Download MS PowerPoint Slide 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.
Topics & Concepts
ProdrugIn vivoPharmacokineticsPharmacologyMutantMedicineOral administrationIn vitroCancer researchKRASChemistryCancerBiologyInternal medicineBiochemistryGeneticsGeneColorectal cancerProtein Kinase Regulation and GTPase SignalingEnzyme Structure and FunctionHER2/EGFR in Cancer Research