Targeting EGFR allosteric site with marine-natural products of Clathria Sp.: A computational approach
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ABSTRACT:
SUBMITTER: Nurisyah
PROVIDER: S-EPMC10821630 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project 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 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.
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Project description:BackgroundThe epidermal growth factor receptor (EGFR) inhibitors represent the first-line therapy regimen for non-small cell lung cancer (NSCLC). Most of these inhibitors target the ATP-site to stop the aggressive development of NSCLC. Stabilization of the ATP-binding on EGFR is difficult due to autophosphorylation of the EGFR domain. This leads to activation of nonintrinsic influence of the tumor microenvironment and expression of anti-apoptotic pathways and drug resistance.MethodsThe NSCLC related literature search was carried out using online databases such as Scopus, Web of Sciences, PubMed, Protein Data Bank and UniPort for the last ten years and selected articles are referred for discussion in this review.ResultsTo overcome the problem of mutations in NSCLC, the allosteric site of EGFR was targeted, which shows significant therapeutic outcome without causing resistance. Compounds like EAI001, EAI045 JBJ-04-125-02, DDC4002 and a series of small molecules with an affinity towards the EGFR allosteric site are reported and are under the investigational stage. These compounds are categorized under fourth-generation anti-NSCLC agents.ConclusionComposition of this review highlights the advantage of inhibiting allosteric site in the EGFRTK receptor domains and presents a comparative analysis of the new fourth-generation anti-NSCLC agents to overcome the drug resistance.
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Project description:The exploration of biologically relevant chemical space for the discovery of small bioactive molecules present in marine organisms has led not only to important advances in certain therapeutic areas, but also to a better understanding of many life processes. The still largely untapped reservoir of countless metabolites that play biological roles in marine invertebrates and microorganisms opens new avenues and poses new challenges for research. Computational technologies provide the means to (i) organize chemical and biological information in easily searchable and hyperlinked databases and knowledgebases; (ii) carry out cheminformatic analyses on natural products; (iii) mine microbial genomes for known and cryptic biosynthetic pathways; (iv) explore global networks that connect active compounds to their targets (often including enzymes); (v) solve structures of ligands, targets, and their respective complexes using X-ray crystallography and NMR techniques, thus enabling virtual screening and structure-based drug design; and (vi) build molecular models to simulate ligand binding and understand mechanisms of action in atomic detail. Marine natural products are viewed today not only as potential drugs, but also as an invaluable source of chemical inspiration for the development of novel chemotypes to be used in chemical biology and medicinal chemistry research.
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