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Open AccessArticle

Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death

1
Scientific 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
2
Plate-forme MicroPICell SFR Santé F. Bonamy-FED 4203/Inserm UMS016/CNRS UMS3556, 44007 Nantes, France
3
Scientific-Production Centre “Armbiotehnologiya”, National Academy of Sciences of the Republic of Armenia, Yerevan 0019, Armenia
4
Départment de Biologie, Université Evry, INSERM, SABNP, Université Paris-Saclay, 91025 Evry, France
5
Faculté des Sciences Fondamentales et Biomédicales, Université Paris Descartes, UMR 8601, CBMIT, 75006 Paris, France
6
IICiMed, Faculté de Pharmacie, Université de Nantes, 44035 Nantes, France
7
Synsight, 91000 Evry, France
8
IICiMed, Faculté des Sciences et des Techniques, Université de Nantes, 44032 Nantes, France
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1094; https://doi.org/10.3390/cancers11081094
Received: 24 May 2019 / Revised: 25 July 2019 / Accepted: 29 July 2019 / Published: 1 August 2019
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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. View Full-Text
Keywords: cancer; targeting chemotherapy; receptor tyrosine kinase; allosteric site; protein degraders; autophagy; cytoskeleton; anoikis; EGFR; Bim cancer; targeting chemotherapy; receptor tyrosine kinase; allosteric site; protein degraders; autophagy; cytoskeleton; anoikis; EGFR; Bim
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Iradyan, M.; Iradyan, N.; Hulin, P.; Hambardzumyan, A.; Gyulkhandanyan, A.; Alves de Sousa, R.; Hessani, A.; Roussakis, C.; Bollot, G.; Bauvais, C.; Sakanyan, V. Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death. Cancers 2019, 11, 1094.

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