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Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death
Melkon Iradyan1, Nina Iradyan1, Philippe Hulin2
1Scientific Technological Centre of Organic and Pharmaceutical Chemistry, Institute of Fine Organic Chemistry after A. L. Mndzhoyan, National Academy of Sciences of the Republic of Armenia, Yerevan 0014, Armenia.
Abstract:
Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKI) has been widely exploited to disrupt aberrant phosphorylation flux in cancer. However, a bottleneck of potent TKIs is the acquisition of drug resistance mutations, secondary effects, and low ability to attenuate tumor progression. We have developed an alternative means of targeting EGFR that relies on protein degradation through two consecutive routes, ultimately leading to cancer cell 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 phosphorylation and induce strong endocytic degradation of the receptor in cancer cells. The compound-promoted depletion of EGFR resulted in the sequestration of non-phosphorylated Bim, which no longer ensured the integrity of the cytoskeleton machinery, as shown by the detachment of cancer cells from the extracellular matrix (ECM). Of particular note, the longer CH3(CH2)n chains in the terminal moiety of the anti-EGFR molecules confer higher hydrophobicity in the allosteric site located in the immediate vicinity of the catalytic pocket. Small compounds accelerated and enhanced EGFR and associated proteins degradation during EGF and/or glutamine starvation of cultures, thereby demonstrating high potency in killing cancer cells by simultaneously modulating signaling and metabolic pathways. We propose a plausible mechanism of anti-cancer action by small degraders through the allosteric site of EGFR. Our data represent a rational and promising perspective in the treatment of aggressive tumors.
Insights
New furfuryl-based compounds target the epidermal growth factor receptor (EGFR) by inducing protein degradation, offering a novel approach to cancer treatment beyond traditional tyrosine kinase inhibitors (TKIs). This method leads to cancer cell death via detachment from the extracellular matrix.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptor (EGFR) is a key target in cancer therapy, often inhibited by tyrosine kinase inhibitors (TKIs).
- TKIs face challenges including drug resistance, secondary effects, and limited tumor progression control.
- Alternative strategies for targeting EGFR are needed to overcome these limitations.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting EGFR through protein degradation.
- To investigate the anti-cancer effects of specific furfuryl derivatives designed to induce EGFR degradation.
- To elucidate the mechanism of action for these novel EGFR degraders.
Main Methods:
- Synthesis and characterization of novel furfuryl derivatives of 4-allyl-5-[2-(4-alkoxyphenyl)-quinolin-4-yl]-4H-1,2,4-triazole-3-thiol.
- Assessment of EGFR binding, tyrosine phosphorylation inhibition, and endocytic degradation in cancer cells.
- Analysis of downstream effects on Bim sequestration, cytoskeleton integrity, and cancer cell detachment from the extracellular matrix (ECM).
- Evaluation of compound efficacy under EGF and/or glutamine starvation conditions.
Main Results:
- The developed furfuryl derivatives bind to EGFR and induce its degradation via endocytosis, independent of strong kinase inhibition.
- EGFR depletion leads to Bim sequestration and subsequent cancer cell detachment from the ECM.
- Compounds with longer alkyl chains exhibit increased hydrophobicity and enhanced degradation of EGFR and associated proteins.
- The compounds effectively kill cancer cells by simultaneously modulating signaling and metabolic pathways.
Conclusions:
- Novel furfuryl derivatives offer a promising alternative to TKIs by inducing EGFR protein degradation.
- This protein degradation approach leads to cancer cell death through cytoskeleton disruption and detachment.
- The findings suggest a new mechanism of anti-cancer action targeting the allosteric site of EGFR, with potential for treating aggressive tumors.
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