Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation

[Image: see text] 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...

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Detalles Bibliográficos
Autores principales: Ji, Xiang, Li, Yan, Kong, Xianqi, Chen, Dawei, Lu, Jiasheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9948199/
https://www.ncbi.nlm.nih.gov/pubmed/36844555
http://dx.doi.org/10.1021/acsomega.3c00329
Descripción
Sumario:[Image: see text] 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.

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