Dataset Information

Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS^G12D Mutation.

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.

SUBMITTER: Ji X

PROVIDER: S-EPMC9948199 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Ji Xiang X Li Yan Y Kong Xianqi X Chen Dawei D Lu Jiasheng J

ACS omega 20230209 7

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 ...[more]

PMID: 36844555

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Project description:Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Studies have shown that CRC patients with KRAS mutations, especially KRASG12D, have an increased risk of metastasis. Emerging evidence indicates that long non-coding RNAs (lncRNAs) are crucial in the carcinogenesis and progression of various cancers, regulating multiple biological processes but the link between KRASG12D mutations and lncRNAs in CRC remains unclear. Therefore, this study was designed to identify a novel lncRNA involved in KRASG12D-mutated CRC and to elucidate its molecular mechanisms. The analysis of differentially expressed lncRNAs in the GSE201412 dataset revealed that LINC02159 was significantly upregulated following treatment with the KRASG12D inhibitor MTRX1133 Data from the GTEx database indicated that LINC02159 is highly expressed in CRC tumour tissues and is associated with better patient outcomes. In vitro and in vivo experiments suggest that LINC02159 acts as a tumour suppressor in CRC progression. Specifically, LINC02159 knockdown negated the inhibitory effects of MRTX1133 on tumourigenesis and its promotive effect on ferroptosis in KRASG12D-mutated CRC cells. LINC02159 expression is regulated by METTL14, with METTL14 knockdown decreasing m6A methylation of LINC02159, leading to its increased expression in CRC cells. Additionally, LINC02159 stabilised FOXC2 expression through de-ubiquitination. Rescue experiments further clarified that the METTL14/LINC02159/FOXC2 signalling axis is crucial for the inhibitory effects of MRTX1133 in KRASG12D-mutated CRC. Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRASG12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.

Dataset Information

Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS^G12D Mutation.

Publications

Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS<sup>G12D</sup> Mutation.

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