Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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 spares not only the unreactive Gly12 residue in the K-Ras wild-type protein but also strong nucleophiles such as the Cys12 residue in K-Ras(G12C). The preference for a weak nucleophile carboxylic acid over canonically stronger nucleophiles provides the basis to expand the covalently targetable proteome to aspartic and glutamic acids.
DOI: 10.1021/jacs.5c06745
Authors: Qinheng Zheng, Kevan M. Shokat
Institution: Howard Hughes Medical Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4411788052