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

Cancers
Melkon IradyanVehary Sakanyan

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 a...Continue Reading

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Citations

Jul 16, 2020·Pharmacological Reports : PR·Swastika MaityYogendra Nayak
Oct 10, 2020·Signal Transduction and Targeted Therapy·Nan YaoWen-Cai Ye
Feb 10, 2021·Biochemistry·Julie K L SinclairAlanna Schepartz

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