posted on 2021-11-17, 16:38authored byGabriele Fumagalli, Rodrigo J. Carbajo, J. Willem M. Nissink, Jonathan Tart, Rongxuan Dou, Andrew P. Thomas, David R. Spring
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.