Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/8/1094 |
| _version_ | 1797714785583759360 |
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| author | Melkon Iradyan Nina Iradyan Philippe Hulin Artur Hambardzumyan Aram Gyulkhandanyan Rodolphe Alves de Sousa Assia Hessani Christos Roussakis Guillaume Bollot Cyril Bauvais Vehary Sakanyan |
| author_facet | Melkon Iradyan Nina Iradyan Philippe Hulin Artur Hambardzumyan Aram Gyulkhandanyan Rodolphe Alves de Sousa Assia Hessani Christos Roussakis Guillaume Bollot Cyril Bauvais Vehary Sakanyan |
| author_sort | Melkon Iradyan |
| collection | DOAJ |
| description | 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 CH<sub>3</sub>(CH<sub>2</sub>)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. |
| first_indexed | 2024-03-12T07:56:52Z |
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| id | doaj.art-69abee0c9bfe4eb5b860c6e1d844d705 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:56:52Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-69abee0c9bfe4eb5b860c6e1d844d7052023-09-02T20:06:36ZengMDPI AGCancers2072-66942019-08-01118109410.3390/cancers11081094cancers11081094Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted DeathMelkon Iradyan0Nina Iradyan1Philippe Hulin2Artur Hambardzumyan3Aram Gyulkhandanyan4Rodolphe Alves de Sousa5Assia Hessani6Christos Roussakis7Guillaume Bollot8Cyril Bauvais9Vehary Sakanyan10Scientific 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, ArmeniaScientific 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, ArmeniaPlate-forme MicroPICell SFR Santé F. Bonamy-FED 4203/Inserm UMS016/CNRS UMS3556, 44007 Nantes, FranceScientific-Production Centre “Armbiotehnologiya”, National Academy of Sciences of the Republic of Armenia, Yerevan 0019, ArmeniaDépartment de Biologie, Université Evry, INSERM, SABNP, Université Paris-Saclay, 91025 Evry, FranceFaculté des Sciences Fondamentales et Biomédicales, Université Paris Descartes, UMR 8601, CBMIT, 75006 Paris, FranceFaculté des Sciences Fondamentales et Biomédicales, Université Paris Descartes, UMR 8601, CBMIT, 75006 Paris, FranceIICiMed, Faculté de Pharmacie, Université de Nantes, 44035 Nantes, FranceSynsight, 91000 Evry, FranceSynsight, 91000 Evry, FranceIICiMed, Faculté de Pharmacie, Université de Nantes, 44035 Nantes, FranceTargeting 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 CH<sub>3</sub>(CH<sub>2</sub>)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.https://www.mdpi.com/2072-6694/11/8/1094cancertargeting chemotherapyreceptor tyrosine kinaseallosteric siteprotein degradersautophagycytoskeletonanoikisEGFRBim |
| spellingShingle | Melkon Iradyan Nina Iradyan Philippe Hulin Artur Hambardzumyan Aram Gyulkhandanyan Rodolphe Alves de Sousa Assia Hessani Christos Roussakis Guillaume Bollot Cyril Bauvais Vehary Sakanyan Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death Cancers cancer targeting chemotherapy receptor tyrosine kinase allosteric site protein degraders autophagy cytoskeleton anoikis EGFR Bim |
| title | Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death |
| title_full | Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death |
| title_fullStr | Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death |
| title_full_unstemmed | Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death |
| title_short | Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death |
| title_sort | targeting degradation of egfr through the allosteric site leads to cancer cell detachment promoted death |
| topic | cancer targeting chemotherapy receptor tyrosine kinase allosteric site protein degraders autophagy cytoskeleton anoikis EGFR Bim |
| url | https://www.mdpi.com/2072-6694/11/8/1094 |
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