Targeting a Novel KRAS Binding Site: Application of One-Component Stapling of Small (5-6-mer) Peptides

Ras proteins are central in the proliferation of many types of Cancer, but a general approach toward the identification of pan-mutant Ras inhibitors has remained unresolved. In this work, we describe the application of a binding pharmacophore identified from analysis of known Ras binding Peptides to the design of novel Peptides. Using a chemically divergent approach, we generated a library of small stapled Peptides from which we identified compounds with weak binding activity. Exploration of structure-activity relationships (SARs) and optimization of these early compounds led to low-micromolar binders of KRAS that block nucleotide exchange.