Accelerated Identification of Cell Active KRAS Inhibitory Macrocyclic Peptides using Mixture Libraries and Automated Ligand Identification System (ALIS) Technology.

ABSTRACT: Macrocyclic peptides can disrupt previously intractable protein-protein interactions (PPIs) relevant to oncology targets such as KRAS. Early hits often lack cellular activity and require meticulous improvement of affinity, permeability, and metabolic stability to become viable leads. We have validated the use of the Automated Ligand Identification System (ALIS) to screen oncogenic KRAS^G12D (GDP) against mass-encoded mini-libraries of macrocyclic peptides and accelerate our structure-activity relationship (SAR) exploration. These mixture libraries were generated by premixing various unnatural amino acids without the need for the laborious purification of individual peptides. The affinity ranking of the peptide sequences provided SAR-rich data sets that led to the selection of nov

SUBMITTER: Garrigou M 

PROVIDER: S-EPMC9289880 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature