Design and synthesis of peptide-drug conjugates to double target EGFR

Targeting either extracellular or intracellular domain of epidermal growth factor receptor (EGFR) to develop novel and potent anticancer drugs is well established. However, targeting both domains is underexplored. Herein, we for the first time report the design of novel peptide-drug conjugates (PDCs) comprising two structural motifs which both extracellularly and intracellularly bind to EGFR. The peptide motif LARLLT was reported to interact with an accessible extracellular surface pocket allosteric from epidermal growth factor (EGF) binding domain while the other motif derived from an EGFR inhibitor Gefitinib was able to occupy the intracellular kinase domain. Among the synthetic PDCs, compound 14c was found as the best to inhibit EGFR phosphorylation compared to the kinase inhibitor motif without the peptide fragment, demonstrating the binding capacity of LARLLT to the EGFR extracellular domain likely contributed to the increase of 14c to inhibit EGFR. Furthermore, 14c inhibited cell proliferation and colony formation of lung cancer cells more effectively than 9c. Taken together, our current work may provide a novel strategy to develop more potent EGFR inhibitors by simultaneously targeting both extracellular and intracellular domains of EGFR.