Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation.

ABSTRACT: Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimi

SUBMITTER: Fulton MD 

PROVIDER: S-EPMC5837902 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature