Peptide‐Based Inhibitors that Target the Docking Site of ERK2

Abstract

AbstractAbnormal kinase activity is highly associated with disease, especially cancer. Thus, kinases are important targets for developing anti‐cancer drugs. The common approach for kinase inhibition is using small molecules that compete with ATP for binding the ATP‐binding site of the kinase. However, since the ATP‐binding site is in many cases common to numerous kinases, it is difficult to achieve selectivity when targeting this site. Here we present an alternative approach of targeting the protein‐protein interactions of kinases as means for achieving selectivity in their inhibition. We demonstrate this approach by using peptides for inhibiting the docking D‐recruitment site (DRS) of the kinase ERK2. We designed a library of peptides, derived from DRS binding sequences of ERK2‐binding proteins. We synthesized the peptides and quantified their interactions with ERK2. Three peptides, derived from the proteins ELK1, SAP1 and SAP2, bound ERK2 in the low micromolar range. These peptides also inhibited the interaction of ERK2 with a surface‐bound ELK1 derived peptide. The peptides penetrated HT29 colon cancer cells and induced a moderate decrease in cell viability. Our approach can be further utilized for developing selective peptide‐based kinase inhibitors.