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[Display omitted] • OTP-3 directly binds to EGFR extracellular domain decreases EGF and EGFR binding affinities by combination with nimotuzumab. • Nimotuzumab combined with OTP-3 exerts growth inhibitory activities in wild-type EGFR cell lines. • Treatment with OTP-3 and nimotuzumab inhibits EGF/EGFR signaling pathway, promotes EGFR degradation. • Combined treatment with OTP-3 and nimotuzumab achieves complete tumor regression in mouse tumor models. Aberrant activation of epidermal growth factor receptor (EGFR) plays a pivotal role in cancer initiation and progression and has gained attention as an anticancer drug target. EGFR monoclonal antibodies have been canonically used in non-small cell lung cancer (NSCLC) treatment. However, a basal level of ligand-independent EGFR signaling pro-survival properties limit the clinical efficacy of EGFR monoclonal antibodies. Therefore, targeting EGFR by inducing degraders is a promising approach towards improving therapeutic efficacy and augmenting the effect of nimotuzumab. Here we describe rational discovery of OTP-3, an oxidized (−)-Epigallocatechin gallate (EGCG) derivative that elicits potent anticancer activity in EGFR wild type NSCLC. Mechanistic studies disclosed that OTP-3 directly binds to EGFR extracellular domain decreases EGF and EGFR binding affinities by combination with nimotuzumab. Molecular docking studies revealed that OTP-3-EGFR is a very stable complex. Further analyses showed that nimotuzumab combined with OTP-3 resulted in significantly promoted EGFR degradation and repressed downstream survival pathways. Accordingly, OTP-3 combined with nimotuzumab significantly inhibits tumor growth through degrading EGFR in vivo. Thus, OTP-3 can also serve as an effective therapeutic agent in NSCLC where it can augment the effects of nimotuzumab, a valuable property for combination agents. [ABSTRACT FROM AUTHOR]