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.