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 antiproliferative activity against certain tumour types in the clinic. Resistance to EGFR inhibitors is mediated by mutation in the ATP site and often through activation of the MAPK pathways by other receptor tyrosine kinases. This inspired the investigation of 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 EGFR inhibitor. A structure-based drug design modeling program, combined with PDB data-mining, protein structural fingerprints and pharmacophore searches was used to help identify and characterize linkers for connecting EGFR-binding moieties to DNA and Src targeting functionalities. The resulting compounds showed EGFR inhibitory potency in the low micromolar to nM range and retained significant activity against their divergent targets.

Exploring EGFR kinase-ligand interactions for optimizing dual action inhibitors

249th National Meeting (2015)

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