Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling.

ABSTRACT: Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure-activity relationship studies involvi

SUBMITTER: Lim S 

PROVIDER: S-EPMC8672774 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature