Denitrogenative Alkylation of K-Ras(G12D) Inhibits Oncogenic Signaling in Cancer Cells.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer. More than 90% of PDAC tumors are caused by KRAS mutations, with the majority expressing the K-Ras(G12D) oncoprotein. Despite extensive drug discovery efforts across academia and industry, there are no approved drugs directly targeting K-Ras(G12D) in a mutant-selective manner. We report a series of α-diazoacetamide compounds that form covalent bonds via denitrogenative alkylation of acquired aspartic acid at the mutation site. The lead molecule allosterically inhibits the mitogen-activated protein kinase pathway downstream of K-Ras and therefore inhibits the growth of KRAS^G12D-driven cancer cell lines but not non-G12D mutation cancer cell lines. Our results show that the diazo-carboxy ligation

SUBMITTER: Zheng Q 

PROVIDER: S-EPMC12272675 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature