Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, researchers in the Kennedy Group, published in Bioorganic & Medicinal Chemistry, 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.
The Kennedy group members 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 optimized using molecular modeling.
Peptides were constrained using peptide “stapling” to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt.
To the group members' knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. Their study presents a novel, alternative targeting site for allosteric inhibition of EGFR.
Conformationally Constrained Peptides Target the Allosteric Kinase Dimer Interface and Inhibit EGFR Activation
Melody D.Fulton, Laura E.Hanold, ZhengRuan, Sneha Patel, Aaron M.Beedle, Natarajan Kannan, Eileen J.Kennedy
Bioorganic & Medicinal Chemistry, Volume 26, Issue 6, 15 March 2018, Pages 1167-1173