Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKI)has been widely exploited to disrupt aberrant phosphorylation flux in cancer. However, a bottleneckof potent TKIs is the acquisition of drug resistance mutations, secondary eects, and low abilityto attenuate tumor progression. We have developed an alternative means of targeting EGFRthat relies on protein degradation through two consecutive routes, ultimately leading to cancercell detachment-related death. We describe furfuryl derivatives of 4-allyl-5-[2-(4-alkoxyphenyl)-quinolin-4-yl]-4H-1,2,4-triazole-3-thiol that bind to and weakly inhibit EGFR tyrosine phosphorylationand induce strong endocytic degradation of the receptor in cancer cells. The compound-promoteddepletion of EGFR resulted in the sequestration of non-phosphorylated Bim, which no longer ensuredthe integrity of the cytoskeleton machinery, as shown by the detachment of cancer cells from theextracellular matrix (ECM). Of particular note, the longer CH3(CH2)n chains in the terminal moiety ofthe anti-EGFR molecules confer higher hydrophobicity in the allosteric site located in the immediatevicinity of the catalytic pocket. Small compounds accelerated and enhanced EGFR and associatedproteins degradation during EGF and/or glutamine starvation of cultures, thereby demonstratinghigh potency in killing cancer cells by simultaneously modulating signaling and metabolic pathways.We propose a plausiblemechanismof anti-cancer action by small degraders through the allosteric site ofEGFR. Our data represent a rational and promising perspective in the treatment of aggressive tumors.