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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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
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author Ji, Xiang
Li, Yan
Kong, Xianqi
Chen, Dawei
Lu, Jiasheng
author_facet Ji, Xiang
Li, Yan
Kong, Xianqi
Chen, Dawei
Lu, Jiasheng
author_sort Ji, Xiang
collection PubMed
description [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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spelling pubmed-99481992023-02-24 Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation Ji, Xiang Li, Yan Kong, Xianqi Chen, Dawei Lu, Jiasheng ACS Omega [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. American Chemical Society 2023-02-09 /pmc/articles/PMC9948199/ /pubmed/36844555 http://dx.doi.org/10.1021/acsomega.3c00329 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Ji, Xiang
Li, Yan
Kong, Xianqi
Chen, Dawei
Lu, Jiasheng
Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation
title Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation
title_full Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation
title_fullStr Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation
title_full_unstemmed Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation
title_short Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS(G12D) Mutation
title_sort discovery of prodrug of mrtx1133 as an oral therapy for cancers with kras(g12d) mutation
url 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
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