The epidermal growth factor receptor (EGFR) is implicated in many cancers, and its kinase activity is the target of commercial anti-cancer agents such as Tarceva and Iressa. However, despite their effectiveness, EGFR kinase inhibitors often show only moderate anti-proliferative activity against certain tumor types in the clinic. This inspired the investigation of dual action therapeutic agents directed not only at EGFR kinase but also at divergent targets such as Src kinase or DNA, with the purpose of producing single compounds termed “combi-molecules”, with greater potency than the single-mode EGFR inhibitor. A structure-based drug design modeling program, combined with PDB data-mining and protein structural fingerprints was used to help identify and characterize inhibitor design motifs for the development of combi- molecules. The resulting combi-molecules showed EGFR inhibitory potency in the low micromolar to nM range as well as DNA cross-linking activity.

Targeting specific interactions to improve EGFR-ligand binding

253rd National Meeting (2017)

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